Elevated risk for CV events in adulthood seen with children on GH therapy
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Children in Sweden who were treated with recombinant human growth hormone, or rhGH, have an increased risk for cardiovascular events in adulthood vs. controls; however, the absolute risk remains low, according to study data.
“We have found an association of childhood GH treatment and later CV morbidity after long-term follow-up — up to 25 years — and after matching and adjusting for many important potential confounders,” Anders Tidblad, MD, PhD, head of the pediatric endocrinology department at Karolinska University Hospital in Stockholm, told Healio. “However, even if the relative risks at a group level are elevated, the absolute risks for the individual patients are still low. Furthermore, an association does not equal a causal relationship, but we must continue to stay vigilant for possible negative long-term effects of this treatment to certain patients.”
In a study published in JAMA Pediatrics, Tidblad and colleagues conducted a nationwide register-based cohort study of CV events among Swedish children treated with rhGH from 1985 to 2010. Individuals in the Swedish National GH Register for Children and clinical rhGH trials were combined to form the GH cohort. Data on treatment variables were obtained from the GH-SAFETY database, and information on adult treatment with rhGH was collected from the Swedish Prescribed Drug Register. Each GH participant was matched for sex, birth year and geographic region with 15 control individuals randomly selected by Statistics Sweden from the Swedish Total Population Register. Data on first CVD events were obtained from the Swedish Patient Register and the Swedish Cause of Death Register.
A total of 3,408 children who received rhGH were matched with 50,036 controls. The median follow-up time was 14.9 years. There were 1,809 total first CVD events recorded, with the GH cohort having 25.6 events per 10,000 person-years and the control group having 22.6 incidents per 10,000 person-years. First CVD events were higher among female patients in the GH group compared with controls, but incidence rates for male patients were similar between the two groups.
The GH cohort had a slightly higher risk for having a first CVD event during follow-up than the control group in unadjusted analysis (HR = 1.13; 95% CI, 0.95-1.36). In a model adjusting for sex, birth length, birth weight, gestational age, age and height at study start, and parental educational level and income, the risk increased for the GH group (adjusted HR = 1.69; 95% CI, 1.3-2.19). Female patients in the GH group had a higher increased risk (HR = 2.05; 95% CI, 1.31-3.2) than male patients (HR = 1.55; 95% CI, 1.12-2.13).
The GH cohort was divided into three subgroups treated for isolated GH deficiency, small for gestational age and idiopathic short stature. The small for gestational age cohort had the highest risk for first CVD events (HR = 1.97; 95% CI, 1.28-3.04), followed by the isolated GH deficiency group (HR = 1.66; 95% CI, 1.21-2.26) and the idiopathic short stature group (HR = 1.55; 95% CI, 1.01-2.37).
There were 167 total first severe CVD events recorded during the follow-up period, with the GH cohort having an incidence rate of 3.48 per 10,000 person-years and the control group 1.97 per 10,000 person-years. The GH group had an increased risk for severe CVD in both the unadjusted (HR = 1.75; 95% CI, 1.08-2.87) and fully adjusted models (aHR = 2.27; 95% CI, 1.01-5.12) compared with controls. However, in a restricted model adjusting only for sex, age and height, the difference between the two groups was not significant.
“Individual patients should not be too alarmed considering the low absolute risks up to 25 years after childhood GH treatment,” Tidblad said about the findings. “However, as a physician, one should always include potential long-term side effects in the overall risk-benefit discussion with the patients and families before treatment initiation as well as stay alert for early manifestations of CVD if previously treated.”
In an editorial published in JAMA Pediatrics, Adda Grimberg, MD, professor of pediatrics at the Perelman School of Medicine at the University of Pennsylvania and scientific director of the Diagnostic and Research Growth Center at Children's Hospital of Philadelphia, wrote that the study sheds some light on risks associated with GH therapy. Indirect evidence supports the potential for detrimental effects from increased GH action, and direct evidence of GH treatment safety contains major limitations, Grimberg wrote. With more children in the U.S. receiving GH therapy, an on-going review into the findings and remaining gaps of GH safety data are needed.
“Frank review of the current knowledge base and its limitations is required to enable patients and their families to make appropriately informed decisions,” Grimberg wrote. “The centrality of treatment safety to patient-family decision-making underscores the importance of continued scrutiny of growth hormone safety as the treatment and its recipients continue to evolve.”
Perspective
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Tidblad and colleagues conducted a very important study analyzing the association between childhood growth hormone therapy and cardiovascular events in adulthood. Due to the nature of the national health system analyzed, very accurate and complete exposure and outcome data are available for treated and control individuals. Through careful analysis of these data while controlling for important confounding factors, the authors show a small, but statistically significantly increased incidence and hazard ratio for cardiovascular events in GH-treated individuals compared to controls. The increased risk was highest in females and individuals born small for gestational age.
The fact that individuals with short stature and those born small for gestational age are known to have an underlying increased risk of CV events in adulthood makes it difficult to determine whether childhood GH therapy causes a change in that risk. However, the fact that longer duration of therapy and the highest category of cumulative GH dose had higher hazard ratios strengthens that argument.
This study strengthens the argument that certain subsets of adults who received GH as children may warrant closer monitoring, and possibly more aggressive intervention, for CVD. In addition, these results emphasize the need for long-term studies of CV health of adults who received childhood GH therapy.
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