Growth Hormones in Kids Linked to Stroke in Young Adults

Pam Harrison

August 18, 2014

The use of growth hormone for the treatment of short stature or growth hormone deficiency in childhood may increase the long-term the risk for stroke in young adulthood, hemorrhagic strokes in particular, French registry data show.

Investigators at the University of Lorraine in France found a significantly higher risk for stroke among patients treated with growth hormone in childhood compared with 2 population-based registries used as reference controls.

The excess risk for stroke was mainly attributable to a "very substantially and significantly higher risk" of hemorrhagic stroke, at a standardized incidence ratio (SIR) ranging from 3.5 to 7.0, depending on the registry rates considered.

The study was published online August 13 in Neurology.

Detailed Study

"In 2012, we analyzed the same French cohort of subjects treated with growth hormone for short stature or idiopathic growth hormone deficiency which revealed larger numbers of death from cerebral vascular accidents (CVAs), including brain and meningeal hemorrhages in particular in treated individuals," lead investigator, Joël Coste, MD, PhD, head of the biostatistics and epidemiology unit at Hotel Dieu, University of Paris, France, told Medscape Medical News.

"This finding justified a more detailed study, focusing in particular on the frequency of non-lethal CVAs in this population. And we observed a significant increase in CVA risk, with treated individuals 1.5 to 5.3 times more likely to experience a CVA than individuals from the general population."

The earlier study was published in the Journal of Clinical Endocrinology and Metabolism (2012;97:416-25).

For both studies, investigators mined the French study the Safety and Appropriateness of Growth hormone treatments in Europe (SAGhE) for cerebrovascular morbidity data in a population-based cohort of patients treated with growth hormone.

They specifically studied the incidence of stroke and all stroke subtypes, including subarachnoid hemorrhage, intracerebral hemorrhage, and ischemic stroke, in this cohort.

Only children who had been exclusively treated with recombinant growth hormone until 1996 were included.

Investigators also limited the analysis to low-risk children including those who were treated for idiopathic isolated growth hormone deficiency, idiopathic short stature, short stature in children born short for gestational age, or isolated growth hormone deficiency associated with a minor craniofacial malformation.

In total, 6874 children were included in this low-risk group. Most children in the group were treated for isolated growth hormone deficiency, determined by a growth hormone stimulation test (peak <10 ng/mL).

The mean age at treatment onset was 11 years, and the mean duration of treatment was 3.9 years. The mean follow-up interval between initiation of treatment and the date of the last follow-up, event, or death was 17.4 years.

A total of 18 events were identified in this previously low-risk group of children, 11 of which were finally validated as incident cases of stroke by hospital reports and imaging results.

Specifically, there were 5 subarachnoid hemorrhages, 3 intracerebral hemorrhages, and 3 ischemic strokes. Three of the patients had been small for gestational age but none had had severe growth hormone deficiency.

The mean age at the time of stroke was 24.2 years, and 4 patients died, including 3 who had a subarachnoid hemorrhage.

Risk/Benefit Assessment

Investigators then used a special statistical method, the "capture-recapture" model, to account for patients for whom it was not possible to obtain information about possible nonfatal CVAs.

Using this model, "the estimated total number of incident strokes was 16.3," investigators report — 11 cases detected at an estimated 5.3 cases missed.

Similarly, the estimated number of missed intracerebral hemorrhages was 4.9, yielding an estimated total of 12.9 incident hemorrhagic strokes in the growth hormone cohort.

The authors found an increased incidence of stroke relative to the 2 population-based registries, with an SIR of 2.2 to 5.3 for all stroke subtypes and an SIR of 5.7 to a 7.0 for hemorrhagic stroke.

Table. SIRs for Different Stroke Subtypes

Stroke Subtype SIR
Dijon registry  
  Hemorrhagic stroke 3.5
  Subarachnoid hemorrhage 5.7
  Intracerebral hemorrhage 2.1
  Ischemic stroke 0.6
Oxford registry  
  Hemorrhagic stroke 4.4
  Subarachnoid hemorrhage 6.3
  Intracerebral hemorrhage 2.9
  Ischemic stroke 2.4

 

"For children and adolescents currently on growth hormone treatment, parents should not stop the treatment without medical advice," said Dr. Coste.

"And in the case where growth hormone is being used merely for the treatment of short stature, the benefits of gaining a few centimetres in growth should be assessed against the risk."

"Much Anticipated" Report

In an accompanying editorial, extract Rebecca Ichord, MD, University of Pennsylvania, Philadelphia, noted that this report has been "much anticipated" by the endocrinology community because it extends and clarifies findings in the 2012 SAGhE study, which showed an increase in mortality in adults treated in childhood with growth hormone.

"Major strengths [of the current study] include the large sample size arising from a mandatory large national treatment registry and the long duration of follow-up," Dr. Ichord observed.

At the same time, Dr. Ichord acknowledged that there are limitations of the study, including uncertainty regarding a causal relationship between growth hormone and hemorrhagic stroke and the small absolute number of events. (Both of these limitations were acknowledged by the authors themselves.)

Despite these limitations, "the implications for clinical practice are potentially urgent and immediate," Dr. Ichord writes. Based on the available data, practitioners who prescribe growth hormone should consider the potential risk for long-term stroke in their counseling about risks and weigh this risk in their own recommendations when determining "net benefit" to the patient.

It may also be prudent to counsel these patients about the importance of primary prevention strategies for cerebrovascular risk factors throughout adult life, she adds.

"The concept of negligible risk is a standard by which treatments given to healthy children at very high cost should be judged," she concludes. "Even a very small increase in risk of a condition with fatal or severely disabling consequences violates this standard."

The study was funded by the French drug safety agency (AFSSAPS), the French Ministry of Health, the Institut National du Cancer and a Commission of European Communities Grant. Dr. Coste and Dr. Ichord have disclosed no relevant financial relationships.

Neurology. Published online August 13, 2014. Abstract Editorial

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