New Evidence-based Clinical Guidelines Help to Navigate Growth Disorders

For a child with stunted height, growth hormone treatments can suggest more than just a taller stature: As routine injections of the synthetic protein work to fuel steady cell production in their bodies, the physical gain can evoke a range of social opportunities that previously felt out of reach. Unfortunately, it can also present pediatric endocrinologists with a dilemma.

Not every child responds to growth hormone (GH) treatment, nor should every child receive it. Despite approval from the Food and Drug Administration to treat a range of conditions with GH therapy, managing children with growth failure comes rife with questions of long-term safety, ethical knots, and a lack of consolidated research.

“Every decision in medicine is a risk-benefit analysis,” said Adda Grimberg, MD, pediatric endocrinologist at Children’s Hospital of Philadelphia.

On behalf of the Pediatric Endocrine Society (PES), Dr. Grimberg and six other pediatric endocrinologists – along with a bioethicist and a GRADE methodologist – issued new clinical guidelines for the administration of GH therapy earlier this year. The guidelines are published in Hormone Research in Paediatrics, the official journal of the pediatric endocrine societies of North America, Europe, and South America. They offer evidence-based recommendations bolstered by endorsements from the PES Drug and Therapeutics Committee as well as the PES Ethics Committee – the latter of which has never been included in previous GH recommendations. The guidelines differ from those last issued in 2003 in that they address new demands for medicine to carry the weight of research and data-based answers.

“Since the Institute of Medicine published their recommendations for improving quality and value in U.S. healthcare, there really is an emphasis on evidence-based decision-making,” Dr. Grimberg said. “The current standard for developing guidelines is to include a systematic review and transparent reporting of the quality and quantity of the evidence supporting any recommendations made. For each point we ask, ‘What is the evidence behind that?’”

Collecting the Evidence

The new guidelines offer distinctly separate recommendations for three growth conditions: growth hormone deficiency (GHD), primary IGF-I deficiency (PIGFD), and idiopathic short stature (ISS).

“Due to diagnostic challenges, the boundaries between these conditions are a little blurred, and patients are a little overlapped,” Dr. Grimberg said.

The paper thus outlines criteria and considerations to help physicians establish diagnoses and navigate the proper treatment. For the first time, the guidelines also address the use IGF-I hormone, a therapy that is one step downstream from GH treatment in terms of signaling, and is often more appropriate to treat PIGFD.

After a rigorous review of more than 15,000 citations based on key questions and guiding principles, the final version of the guidelines takes a measured and cautious approach to GH treatment. If a child has true growth hormone deficiency, wherein their body doesn’t produce enough of the powerful protein, the authors “strongly recommend” the use of GH. Collective data demonstrate that over 4,520 patients prescribed GH treatment from multiple studies and registries reached an adult height on par with their genetic potential. Growth hormone deficiency can also result in weaker bones, impaired cardiac performance, and unfavorable lipid profiles. The authors found that while results on cardiac function and lipid profiles were inconsistent, GH therapy did indeed improve bone density and bone composition for children with GHD.

If other factors besides growth hormone deficiency cause short stature, the authors recommend careful considerations for each individual case. If a child has PIGFD, for example, in which their bodies show normal levels of growth hormone but lack the insulin-like growth factor that allows them to make use of that growth hormone, the authors recommend first ruling out any nutritional problems, then turning to IGF-I therapy in severe cases.

Finally, if a child has ISS, in which they have a significantly shorter height than average with no known cause, the authors recommend avoiding the routine use of GH and instead making an informed decision based on each child’s physical and psychological situation. Studies show that not all individuals with ISS respond to treatment, placing them at risk for unknown side effects without any obvious benefit. This uncertainty draws attention to one of the most salient reasons for why we need stricter clinical guidelines: the lack of evidence behind GH therapy’s long-term safety.

Identifying the Knowledge Gaps

Experts simply don’t know how GH therapy in childhood and adolescence affects the body as it ages over time, Dr. Grimberg said. Patients who started receiving recombinant growth hormone when it first became commercially available in 1985 would only be in their 40’s today, and scientists lack sufficient data on those adults. Existing data are conflicted: In a European consortium study of adults with a history of pediatric growth hormone treatment, the French subgroup reported that GH resulted in increased mortality and stroke while subgroups from other countries did not. This uncertainty must be weighed against the potential benefit of treating healthy short children.

“If you have growth hormone deficiency, there are health reasons for wanting to replace the growth hormone, and it’s not just about height,” Dr. Grimberg said. “It’s not controversial, and you treat. When you have healthy short kids who have idiopathic short stature and want to be taller, however, you are exposing them to unknown risks down the road. That is an ethical consideration.”

Directing Future Research

Alongside safety, Dr. Grimberg believes that the guidelines highlight two other conceptual gaps that current and future research will work to address. The first relates to outcomes: How exactly should a physician or researcher measure the success of GH therapy? What factors define improved well-being in a GH-treated child?

“If parents are seeking growth hormone because they are afraid short stature leads to psycho-social challenges, is height really the best outcome measure?” Dr. Grimberg asked. “Should we be looking at measures of psychosocial adaptation as the better metric?”

On top of that, most studies only report short-term outcomes because it is difficult and expensive to follow GH-treated children to adult height. Retrospective analyses are tricky to interpret because factors like defining GH deficiency or GH treatment doses and endpoints may have changed over time.

Another conceptual gap lies in the inconsistency of GH testing itself. Assays and dynamic tests to measure GH and IGF-I production have changed over time, and even current tests are flawed and often differ between institutions and studies.

“In retrospective studies, it’s hard for us to cleanly figure out who has what, and then to assess what we are treating and how we are treating it,” Dr. Grimberg said.

In response to these knowledge gaps, Dr. Grimberg’s current work takes a closer look at the disparities in the diagnosis and treatment of children with short stature. Knowing where these disparities arise will help researchers and physicians better address them to improve clinical care. Later this summer, Dr. Grimberg and her colleague expect to release a new paper that details how both the presence and the absence of evidence shaped the current guidelines.

“We need better diagnostic tests and better outcome metrics,” Dr. Grimberg said. “We also need to test treatments to see if they really do or do not improve various outcomes.”

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