A review of biopsychosocial strategies to prevent and overcome early-recognized poor adherence in growth hormone therapy of children

Abstract

Background:

Adherence to growth hormone (GH) therapy among children is variable and remains a problem, possibly affecting growth outcomes and future health, and having economic consequences.

Objective:

To provide a review of the issues related to poor adherence to GH therapy in children and describe integrative strategies that may improve adherence.

Results:

Poor adherence may be caused by various factors, affecting both the children and their families. The key reasons for adherence difficulties are psychological/emotional problems, social/everyday problems and technical handling issues of the drug delivery device. Correspondingly a broad range of strategies to address adherence to GH therapy often revolve around counseling and education, not just for the patient but also for the family giving care.

Limitations:

This review is intended as a general survey of strategies which could help, in clinical practice, to overcome poor adherence to growth hormone therapy in children; it summarizes the representative literature but it does not aim to be a rigorous database literature search in every aspect.

Conclusions:

If poor adherence is recognized early on during treatment, appropriate steps may be taken to identify barriers that are amenable to change for encouraging the child to adhere to the treatment regimen. A preventative approach may also be considered; for example, doctors could address adherence issues early and train families of children treated with GH to recognize the resources as well as the barriers to adherence. The broad range of different causes for poor adherence demands a great variety of interventions, making it important to individualize optimal treatment behavior. Additionally, economic studies are required to quantify the cost of poor adherence to GH therapy and to show the financial benefits of good adherence.

Key words::

• Adherence
• Adherence intervention
• Growth hormone
• Pediatric

Introduction

Growth hormone (GH), secreted by the anterior pituitary gland, modulates growth by increasing chondrocyte proliferation at the epiphyseal growth plates and stimulating production of insulin-like growth factors1,2. GH promotes the growth and development of muscle, bone and other tissues during maturation. GH also influences protein, lipid and carbohydrate metabolism throughout life1. Therefore, apart from short stature, growth hormone deficiency (GHD) can cause hypoglycemia and metabolic disturbances, the consequences of which can persist into adult life and cause long-term sequelae. For example, children born small for gestational age seem to be at risk of long-term conditions, including cardiovascular and metabolic complications3. As long-term treatment with recombinant human GH (rhGH) results in final adult height within the normal range, identifying and treating children with GHD is crucial, particularly in the early years.

Several conditions can cause short stature and impaired growth. Furthermore, GHD is a complex condition with a heterogeneous etiology that potentially complicates diagnosis4. Approximately 5–35% of cases of congenital GHD are related to a genetic defect, resulting in an inability to synthesize GH. GHD may also arise from damage to the pituitary gland, for instance by a tumor or radiation. However, most cases of GHD are idiopathic5. Despite the variety of etiologies, replacement therapy with GH ensures that most children with GHD attain normal adult stature. Furthermore, GH can treat growth retardation due to several other conditions4. However, despite the unequivocal benefits of replacement therapy with GH for most subjects, poor adherence to treatment regimen is common6.

In accordance with the biopsychosocial paradigm of Engel7 referring to a holistic integration of biological, psychological and social factors and dimensions of (chronic) diseases, this review aims to describe the various issues surrounding adherence to GH therapy, including the issues that need to be solved to achieve good adherence. A possible resolution is proposed in the form of support and help to enable healthcare professionals to better assist the families of children treated with GH to cope emotionally as well as handle day-to-day problems.

Poor adherence in chronic diseases and GH therapy

Non-adherence is a common problem during the management of most chronic diseases. Adherence to medication for chronic diseases averages between 50% and 70%8,9. Even in clinical studies, adherence rates may still be only 43–78% in chronic conditions10, and poor adherence undermines clinical and economic outcomes. For example, poor adherence among patients with chronic diseases makes treatment failure11 and hospitalizations more likely, undermines health-related quality of life and increases healthcare costs12. Disease, setting and prognosis seem to have little effect on adherence rates8,9. However, evaluation of adherence to a medication regimen is complicated by several factors, including variability in adherence by individual patients and practical difficulties in monitoring and recording adherence. Different methods for following adherence, ranging from self-report to direct observation by a healthcare professional, vary in reliability, ease of use and cost6. Direct questioning of a patient on adherence can result in over-estimation of adherence, particularly when the patient wishes to please the physician10.

GH therapy is individualized to each patient depending on body surface area or body weight, and should be injected subcutaneously every day. Despite the difficulties in assessing behavior and outcomes, increasing evidence suggests that poor adherence is quite common among people (children and adults) taking GH, with adherence estimated between 36% and 49% during the interval since the last clinic visit13. However, differences in the enrolled populations, experimental design, definitions employed and devices used to administer GH can result in marked variations in adherence between studies. In one study, one in ten children from the United Kingdom treated with GH or their parents admitted missing at least three injections a month14. In a North American study, 13.4% of those receiving GH administered with a needle and syringe missed more than half of their prescribed dose15. Estimates based on prescription data indicate that, of 75 children followed for 12 months, 39% and 23% missed more than one and two injections a week, respectively16. A Spanish study examined adherence patterns in more detail in patients who had been on growth hormone therapy for longer than six months. Adherence was excellent (no missed doses in the period between hospital visits) in 74.0% of subjects, good (<5% missed doses) in 20.1%, fair (5–10%) in 3.4% and poor (>10%) in 2.5%. Socioeconomic status, sex and age did not influence adherence rates. Adherence was excellent in 67.8% and 73.4% of those using conventional and preloaded syringes, respectively, compared with 83.5% and 84.6% with automatic and manual pens, respectively17.

Adherence patterns change during the course of treatment. Several studies have shown that treatment persistence in patients with chronic conditions often decreases during the first year of therapy18–20. Rosenfeld and Bakker reported that teenage subjects have the lowest level of adherence: 23% of adolescents were highly adherent, defined as answering ‘never’ to missing a dose for eight or nine of nine potential reasons, compared with 34% of adults and 36% of children aged between 4 and 12 years in the three-month period immediately preceding the study. Furthermore, 35% of adults, 22% of teenagers and 15% of children were non-persistent – i.e. they had stopped taking treatment for one month to one year or had stopped taking GH completely21. Therefore, ensuring the smooth transition of the patient from a pediatric endocrinologist to an adult endocrinologist is important to maintain adequate adherence because the person takes responsibility for their GH treatment. Indeed, adherence during the first year of treatment as a teenager generally establishes adherence pattern during adolescence6. Consensus guidelines published by the European Society for Pediatric Endocrinology suggest that ‘transition care requires a dedicated service with contributions from pediatric and adult endocrinology’. The guidelines also note that adolescents may experience markedly impaired quality of life and psychosocial problems related to GHD, and some may need counseling. However, the guidelines highlight ‘a pressing need for validated instruments’ that can assess quality of life among adolescents3. The development of such instruments would facilitate cost–utility analyses in this cohort.

The optimal dose of GH that subjects need to receive to attain the best possible outcomes has yet to be quantified and should be the topic of future observational studies. Nevertheless, GH dose and duration of GH treatment are important factors determining adult height in children with GHD22,23 and poor adherence to GH therapy can undermine outcomes16. Desrosiers and colleagues compared outcomes in 305 children treated with GH administered with a needle and syringe and 326 treated with a needle-free device15. Over two years, growth rate, change in height standard deviation score or change in height-for-age did not differ between the two groups. Most children adhered well, with 84.6% of those using the needle-free system and 76.3% of those using needle and syringe missing fewer than three doses per month. However, 6.0% and 13.4%, respectively, missed more than half of their prescribed GH doses. This study indicates that adherence influences outcomes in children taking GH, showing that those who missed more than half of their monthly dose have lower annual growth (6.3 cm per year) than those who missed less than half of their doses (8.9–9.1 cm per year)15. Despite the evidence of this analysis, a specific definition of suboptimal response to GH therapy remains contentious. Further studies with greater numbers of participants and reliable adherence data are required to better understand and quantify the effect of poor adherence on growth outcome. Bakker et al. proposed that height velocity of one standard deviation below the mean target for age represents a ‘poor’ response to GH and, therefore, identifies those who may benefit from dose adjustment, diagnostic review or assessment of adherence24.

Increases in height and changes in height velocity are the most important parameters to assess the response to GH in children with GHD25. However, children may show a suboptimal response for several reasons and, to date, no method can directly assess adherence to GH treatment. Instead of this, more indirect assessments (e.g., parental questionnaires with retrospective, more subjective self-judgments) concerning injections have been applied6. At present, there is one electronic device on the market that monitors when doses of GH are taken and records the data for future evaluation26,27. By recording and storing details of successful injections, the child and parent can be reminded of when the last dose was taken, and the physician can examine injection logs to determine whether doses are being taken as prescribed28. Based on this more objective information, the physician may choose to try to improve adherence to the dosing regimen. However, no comparative studies are available that assessed GH adherence rates with the electronic device compared to either regimens using needles and syringes or needle-free devices. Measurement of biomarkers represents a sensitive and specific (albeit indirect) means to assess adherence to GH29. Insulin-like growth factor 1 (IGF-1) and insulin-like growth factor-binding protein 3 (IGFBP3) are not secreted episodically and have relatively long half-lives2, making these proteins valuable biomarkers. However, the concentrations of IGF-1 and IGFBP3 do not always correlate with the growth response25. Furthermore, the profiles of biomarkers change over time: GH secretion and IGF-1 levels peak during mid-to-late puberty3. Although these temporal changes in biomarker levels can complicate interpretation, healthcare professionals should consider measuring them regularly. Changes in biomarker levels can give an indication of poor or erratic adherence.

Given the costs of GH treatment, healthcare professionals need to make every effort to maximize cost effectiveness13. In fact, a recent estimate indicated that the incremental cost-effectiveness ratio of GH therapy for idiopathic short stature (versus no therapy) was US$52,634 per inch gained (2.54 cm) or $99,959 per child22. The cost per inch gained for GH varied from $38,783 for children showing incremental growth of 2.6 inches (6.6 cm) to $81,875 for growth of 1.2 inches (3.0 cm)21. This study demonstrates that the cost per inch gained is higher in the case of a poor response than in the case of a good response, indicating that any treatment improvement that maximizes the response will also decrease the relative treatment cost. A study in Sweden concluded that the incremental cost per quality-adjusted life-year of GH therapy was SEK 240,831 (∼$37,500) for children born small for gestational age and SEK 120,494 (∼$18,800) for children with GHD, both of which were below the cost-effectiveness threshold30.

As the issue of poor adherence becomes more widely recognized by healthcare professionals, health organizations and the pharmaceutical industry, efforts are being made to consider not just whether the treatment is correct but also to confirm that the treatment is taken. While subjects currently receiving GH may be counseled if poor adherence is suspected, efforts may also be made at initiation of therapy to prevent a future decline in adherence. Due to the heterogeneity of both disease and patient types, strategies to prevent poor adherence may be a valuable asset to doctors and nurses dealing with those who receive GH therapy.

Causes of poor adherence during GH therapy

Poor adherence in people taking GH can arise for several inter-related and mutually reinforcing reasons (Figure 1). Problems to GH therapy adherence vary among people, but fall into three main classes: psychological–emotional problems (related to inadequate understanding of the illness and its treatment); socioeconomic and everyday problems; and technical and handling problems (related to administration of the drug and use of the delivery device).

Figure 1.  Summary of the objective factors and subjective attitudes contributing to adherence issues with GH therapy.

Psychological and emotional factors

Several factors can affect adherence during treatment with GH. First, attaining final adult height takes many years. Therefore, children treated with GH, or their parents, need to maintain their motivation during a course of treatment that may last for over a decade. It is, therefore, important to provide regular encouragement to avoid ‘therapeutic fatigue’. Clinicians should be especially vigilant for difficult motivational issues, especially during specific developmental phases, such as transition periods (e.g., between pediatric and adult endocrinology clinics).

Second, GHD and many other indications for GH are ‘silent’ conditions and follow an unpredictable course. Affected people do not experience obvious symptoms and show a variable prognosis, course and pattern of co-morbidity31. Importantly, non-adherence does not immediately result in serious health problems or pain, or impair physical fitness13. However, non-adherence confers immediate advantages, such as avoiding reminders of the disease, the discomfort or pain associated with injections, and associated lifestyle disruption. Therefore, healthcare professionals need to ensure that the perception of children and parents about the long-term benefits outweighs the short-term disadvantages, using education and the judicious choice of administration device. The inherent unpredictability of GHD or similar conditions means that healthcare professionals need to clarify parents’ expectations, beliefs and goals from the start of treatment with GH. Such expectations may include definition of a successful outcome, psychological characteristics and psychosocial adaptation, ideally agreed in advance with the child, parents or both32. These expectations may also need to be revisited and updated with time; for instance, if an adolescent male persisted in comparing his height with that of the tallest boy in the class, the care team should try to change his expectations towards a more realistic goal.

Children’s and parents’ beliefs about health generally, GHD and GH specifically, as well as their relationships with healthcare professionals, are highly influential in determining adherence. In extreme cases, some people deny that they are ill, disbelieve the diagnosis, have low expectations of GH treatment and fail to perceive the risks associated with poor adherence, partly because these are not immediately apparent. More commonly, some people may not completely adhere because of concerns about side-effects and the disruption to their lifestyle. In other cases, people misunderstand treatment instructions, experience anxiety or become confused over the regimen’s complexity – especially if they suffer from one or more concurrent disease that requires treatment – or simply forget11. Biopsychosocial counseling by the physician or, in severe cases, pediatric psychologists could advise about coping emotionally with GHD and practical problem-solving approaches33. The phases of an individualized counseling/therapy decision process are outlined in Figure 2.

Figure 2.  Phases of the individual counseling/therapy decision.

To understand the issues that each individual faces, healthcare professionals need to engage in open and honest discussions with children and parents to appropriately understand and address the underlying causes of poor adherence. For example, healthcare professionals need to adapt their approach to the child’s and parents’ education level. Adopting a non-judgmental approach ensures effective communication with children and parents. Therefore, healthcare professionals need to develop effective communication skills and acknowledge children’s and parents’ health beliefs and therapeutic expectations as valid, even if they disagree. Healthcare professionals can further improve patients’ adherence by considering patients’ expectations at each clinical visit, and giving frequent feedback and providing self-management plans12.

Improved education is a prerequisite to ensure that children and parents appreciate the importance of good adherence; patient education improves adherence in many conditions and disease severities12. Children and parents also need to translate understanding into behavioral change. Therefore, appropriate motivational support is essential to ensure that children’s and parents’ commitment to GH treatment does not diminish over time27. In some cases, reinforcement during the regular clinical review will suffice. In other cases, healthcare professionals may need to consider more active intervention, such as reminder systems or phone calls by nurses.

Socioeconomic and everyday problems

Healthcare professionals need to be aware of, and sensitive to, the socioeconomic factors that can affect poor adherence. Such factors include poverty, illiteracy and low level of education, unemployment, poor social support networks, dysfunctional family relationships, unstable living conditions, and cost of transport and medication, as well as cultural and lay beliefs about illness and treatment11. Healthcare professionals could address illiteracy or poor education with careful explanations tailored to the patients’ intellectual abilities and educational level. A medical social worker could give advice about social security and other benefits, as well as work with counselors to address issues associated with dysfunctional family and social support.

In many chronic diseases, a seasonal or periodic variation is seen; adherence is typically worse during weekends and between April and September (in a European study)34. Common life events – such as sleepovers, weeks before examinations and changes in jobs or home6, as well as parental separation or divorce35 – can also undermine adherence. Parents do not want to prevent their children participating in social activities, and changes in jobs and home are inevitable. Therefore, discussions with children and parents allow providers to agree individualized strategies that reduce the likelihood of missing a dose because of lifestyle factors and events6.

Therefore, healthcare professionals need to be aware of lifestyle and other factors that could contribute to poor adherence, such as mental handicap, vulnerable developmental stage (particularly as individuals gain increasing autonomy during adolescence) and socioeconomic deprivation. In some cases, medical social workers, psychological counselors and psychotherapists are needed to address these issues. These groups can advise children and parents about coping emotionally with GHD and give practical problem-solving approaches. In some cases, family therapy, additional supervision or attention can help improve adherence36.

The variety of potential problems that can limit adherence suggests that a single intervention is not sufficient. Therefore, several strategies should be available to reduce issues contributing to poor adherence. Healthcare professionals could then select the intervention they consider most appropriate for the individual.

Technical and handling problems

Integration of GH therapy into a family’s lifestyle, which depends on children and parents understanding their roles and responsibilities in the therapy, can be helpful for children treated with GH. A UK study reported that only 40.4% of parents and children showed ‘adequate understanding’ about treatment with GH. Furthermore, 30.3% of parents and children ‘had no clear idea what they were doing’37. The survey also showed ‘major confusion’ regarding the dosage of GH and the amount to inject each day. In one study, only 68% of children taking GH, or their parents, could accurately describe their diagnosis14. In another study, 57.6% of people treated requested more information about GH treatment17. Not surprisingly, subjects with a better understanding were more likely to adhere to treatment37. Errors in dilution and mixing of a drug preparation are important factors contributing to children’s and parents’ poor understanding about treatment37. An open and non-judgmental discussion with children and their parents can identify possible causes of poor adherence, and allow healthcare professionals to tailor treatment and suggest solutions to each individual.

While healthcare professionals, parents and children treated with GH can choose from a growing range of administration devices, GH still requires systemic administration by injection. Healthcare professionals can approach this issue in different ways.

First, they can encourage children to self-inject when they reach an appropriate age, which helps engender a sense of empowerment over their disease and, therefore, can bolster adherence17. Relying on another person to inject undermines the child’s independence and increases the likelihood of missed injections if the family member is not available38. For this reason, it is important to train both parents (if possible) in the administration of GH before the child can self-inject.

Second, up to 22% of the population suffers from needle anxiety and familiarity does not always lead to extinction of the anxiety. In fact, needle phobia and anxiety are more common among people who self-inject than among the general population39. However, training in good injection technique helps limit discomfort and pain6. In a study in Spain, self-injection and training on injection technique from hospital staff helped improve adherence17. Needle-free devices, systems with hidden needles and other innovative ways that make systemic administration less traumatic can reduce needle phobia, anxiety and the discomfort of administration27, which, in turn, can improve adherence.

Choosing the most appropriate device

The choice of device to administer GH should include subject- and treatment-related factors. Matching the device to the needs and attitudes of parents and children by giving them a choice of devices maximizes the chance of adequate adherence without compromising outcomes16,40. Although the identification of factors that affect the choice of device can be difficult41, some studies have shown some trends that could help improve the design of injection devices.

In interviews of 56 children treated with GH and their parents, lack of bruising emerged as the most important factor influencing the choice of injection device. Other important attributes were: auto-injector, lack of pain, lightweight, silent, ease of holding, needle-free, small size and hidden needle41. In another study42, subjects rated reliability, ease of use, lack of pain during injection, safety and the number of steps as the five (of 19) most important attributes for a device to administer GH. Parents, nurses and physicians rated reliability and ease of use as the two most important attributes42. An electronic device was the preferred option among parents (71%), physicians (85%) and nurses (56%)42. Since study respondents regarded lack of pain as the third most important attribute for a GH injection device, the authors suggested that device design features that reduce real pain (e.g., finer needles and adjustable injection speeds) and perceived pain (e.g., needle-free or hidden-needle options and noiseless operation) reduce discomfort and, therefore, improve adherence42. Finally, a recent publication reported the results of a survey conducted with a device which allows the recording of injection data, highlighting that this device provides an accurate method of monitoring adherence with rhGH43.

Consequently, offering people the opportunity to choose their device improves adherence compared with the nurse specialist or consultant allocating the device, without compromising outcomes. For example, Kapoor and colleagues found that there were no significant differences in height velocity among children given a free choice of device16. Notably, diminished height velocity has been associated with reduced adherence to treatment due to a lack of free choice of device at the onset of treatment26. Wickramasuriya and colleagues reported that, when given a free choice, 54% of children chose a device with a needle and 46% preferred a needle-free system40. Although not significantly different, compliance rates were 87% and 96% in those who chose a device with a needle and those who decided to use a needle-free system, respectively. Age, sex or diagnostic category did not significantly influence the choice of device. In this study, ease of use emerged as the factor most likely to determine device choice by subjects. Indeed, ease of use was more influential than the presence of a needle (cited by 36 and 31 of 60 subjects, respectively). Only 4.8% of children subsequently changed device, suggesting that most were satisfied with their choice40.

Strategies to improve adherence

No single intervention optimizes adherence for every individual taking GH, in every setting or in every set of circumstances. Indeed, a systematic review showed that almost all interventions that improved adherence combined several elements, from making management more convenient, providing information, offering counseling, sending reminders, self-monitoring, reinforcement and, in some cases, suggesting family therapy, additional supervision or attention36. Therefore, healthcare professionals may find it beneficial to offer families an individualized approach encompassing various strategies to overcome the many problems that can engender poor adherence (Table 1). Ideally, a nurse or another healthcare professional should educate children, parents or both at home, while the prescribing doctor should ensure that the child received the most appropriate device and optimized regimens for concurrent medication. The family will also need help and advice regarding the technical demands of GH therapy, such as preparing injections.

Table 1.  Features of a patient-oriented procedure for optimization of adherence.

Comprehensive biopsychosocial history of the patient

Provision of medical information and discussion of treatment protocols

Supply of individual resources related to implementation of the physician’s treatment recommendations, based on the patient’s condition and therapy-related demands

Individual personal counseling for improvement of health-related quality of life

Adherence as a continuous treatment goal and challenge for the patient, family and physician, which requires a long-term honest and confidential dialogue between the parties

Child-adjusted therapeutic procedures are likely to produce the highest rates of adherence. The transfer of competencies from healthcare professionals to parents may help to address many factors associated with poor adherence during therapy with GH (Figure 3).

Figure 3.  Transfer of biopsychosocial competences from healthcare professionals to empower patients and parents.

As GHD is predominately a pediatric disease, parents and other informal carers are key to ensure adequate adherence. Therefore, healthcare professionals should receive training in counseling to help children and parents cope with GHD and enable their empowerment over the condition. Physicians should be trained to the latest International Classification of Functioning, Disability and Health (ICF) standards (which correspond to the biopsychosocial paradigm of healthcare by Engel7) to ensure that they recognize early signs of social and everyday problems, and alert supporting services (e.g., social workers) in a timely manner.

Some examples of specific interventions to adherence challenges are presented in Table 2. Given the importance of discussion with the patient to overcome barriers to adherence, healthcare professionals should consider whether they need further training in counseling and communication skills.

Table 2.  Challenges to adherence in GH therapy and associated interventions13,47.

Challenge to adherence	Patient training intervention
Inappropriate concept of treatment	• Restructuring the treatment beliefs
	• Modification/correction of the false beliefs regarding therapy
Lack of knowledge about the treatment	• Offering education regarding the effect of medication and goals of therapy
Impaired treatment skills	• Education and behavioral training to develop independence in administration of treatment
Reduced understanding of treatment	• Training and education to describe the physical effects and changes the treatment will have on the patient
Fear of side-effects from treatment	• Education about possible side-effects
	• Discussion about balancing benefits of therapy with the side-effects
	• Discussion with patients about their experiences
Handling problems in administering treatment	• Explanation and discussion of the process for treatment administration, accompanied by practical examples
	• Selection of the most appropriate injection device with the patient
Questioning efficacy of treatment	• Training of and discussion about the treatment

The open, co-operative, non-judgmental approach facilitates the shared decision-making between healthcare professionals and children or parents41. For example, relationships based on mutual trust between healthcare professionals and children and parents facilitate communication and engender confidence in the professionals’ recommendations, including those related to dosing12. A meta-analysis showed that better physician–patient collaboration improves adherence in various settings including pediatric and adult patients, chronic and acute conditions, and primary care and specialist clinics44. A recent study in New Zealand found that objective measures of adherence, such as counting empty vials returned to the clinic, was significantly correlated with height velocity standard deviation scores45.

Suboptimal performance by healthcare teams can undermine adherence. Therefore, healthcare professionals need to address issues such as a lack of knowledge and training, and failure to provide adequate patient education or follow-up. Several factors associated with inadequate health services – including poor structures, reimbursement and medication distribution, excessive workload, lack of incentives and feedback on performance and short consultations – can compromise adherence11.

Inadequate contact with healthcare professionals potentially contributes to poor adherence21. According to consensus guidelines for the diagnosis and treatment of GHD in childhood and adolescence, healthcare professionals should review patients every three to six months25. Regular contact is important to avoid ‘therapeutic fatigue’27 by reinforcing the importance of good adherence during a course of treatment that can last many years. However, subjects and carers may need advice between appointments. Children and their parents rated a telephone helpline (66 from a maximum score of 100) more highly than they rated nurse support (47 of 100)41. In addition to regular contact provided by a clinic, pharmaceutical companies could provide patient support programs that may range from support specific to the patient’s drug delivery device (supply of needles or advice/replacement in case of a damaged device), to websites that help patients track their injections, to motivational newsletters and emails. Where permitted by local regulations, patients may also seek advice on obtaining reimbursement for their treatment. While these approaches seem logical, future studies need to characterize both the impact and cost effectiveness of support services and interventions that aim to improve adherence, especially as many patients will probably need multiple rather than single approaches.

A comprehensive literature review of the effectiveness and costs associated with interventions to improve adherence in cardiovascular disease, standardized over six months, illustrates a comparison of the relative effectiveness and costs of different approaches to improve adherence46. The interventions produced relative improvements (RI) ranging from 1.11 (mailed reminder to refill the prescription) to 4.65 (management by a community pharmacist). Six-month costs varied from $9.59 (mailed reminder) to $142.22 per patient. The most expensive approach used increased pharmacy care, patient diaries and educational material. Reminders emerged as the least effective approach (RI:1.11–1.14). However, reminders were also the least expensive intervention. Case-management interventions produced the greatest improvement (RI:1.23–4.65), but were also the most costly ($90–130 over six months)46. However, the cost effectiveness of interventions to improve adherence needs to be assessed for GH specifically and stratified by indication, and the time needed to train patients may emerge as an important cost-driver. Training in administration technique by hospital staff has been shown to improve adherence17.

Conclusion

Good adherence during chronic treatment with GH is a prerequisite to obtaining the optimal final height in children with GHD and other indications. However, in many cases adherence is poor. Early and precise monitoring and recording of adherence with GH therapy enables timely initiation of biopsychosocial strategies to encourage self-care and good adherence. Innovative technologies such as electronic injection recording devices as more objective measures of adherence may facilitate discussion about adherence between patients and providers. The resulting communication may more easily identify barriers that are amenable to change. Further studies are needed that quantify the short-term improvement in adherence, the long-term clinical outcome and the relation between adherence and short-term improvement growth outcomes, and the cost effectiveness of interventions that aim to optimize adherence to GH.

Numerous factors contribute to poor adherence with GH. Therefore, healthcare professionals need to individualize specific interventions and their overall approach to overcome the specific problems of each individual that contribute to poor adherence. In all cases, providers should maintain a non-judgmental relationship with the patient and collaborate with parents and children to establish clear goals that represent the successful treatment with GH. Adopting a preventative strategy may also be of great value to build the knowledge, skills and awareness in the family of the child to aid adherence from initiation of therapy, rather than relying on recognition of adherence problems and having to put in place measures to address these matters.

This review is intended as a general outline of potential biopsychosocial strategies which could help to overcome poor adherence to GH therapy in children, with selected references cited to support the views expressed. A rigorous search was not done due to the theoretical nature of the biopsychosocial setting and due to the fact that we did not find empirical studies in this specific context.

Declaration of interest

F.H. has no competing interests. C.G. is an employee of Merck Serono SA Geneva.

Transparency

Declaration of funding

The preparation of this manuscript was funded by Merck Serono International SA (an affiliate of Merck KGaA, Darmstadt, Germany).

Acknowledgments

Editorial assistance for development of this manuscript was provided by Mark Greener of Phase II International, Esher, Surrey, United Kingdom. The authors had full control over the content of the manuscript and take sole responsibility for the final version submitted.