Children who receive growth hormone face a slightly elevated risk of cardiovascular events when they reach adulthood, according to a large study from Sweden. Against a backdrop of one yearly event for every 442 patients who did not receive hormone therapy, the risk rose to 1 in 391 for the 3,408 treated with growth hormone, a significant increase of 69%. Women faced twice the risk, with a hazard ratio of 2.05 versus 1.55 for men, researchers report in JAMA Pediatrics. The longer the duration of treatment and the higher the cumulative dose, the greater the odds of arrhythmias, hypertensive disease, stroke and other problems. However, it was not possible to determine whether the increased risk was directly caused by the treatment or the underlying problems that had sparked the therapy to begin with. And the researchers emphasized that the absolute risk of cardiovascular problems was small. "This is important to remember when evaluating risk for a certain individual," chief author Dr. Anders Tidblad of Karolinska Institute in Stockholm told Reuters Health by email. "What is presented is an association and not evidence of causality. We still do not know for certain if there are other underlying causes for this observed increased risk, even if we have tried as far as possible to handle this issue by having a comparison group as similar as possible and adjusting for important covariates." A French study initially published in 2012 had warned of the potential of cardiovascular mortality and cerebrovascular morbidity. "I believe the French study did stir up a lot of emotions in the community and temporarily might have had a negative effect on new treatment initiations," said Dr. Tidblad, head of the pediatric endocrinology department at Karolinska University Hospital. "But the difficulties to draw firm conclusions from this study made this effect transient." He predicted that "pediatric endocrinologists will welcome our study and appreciate our attempt to address this issue in a nuanced way and come to the conclusion that we need to continue to stay vigilant for potential long-term effects of this treatment." "But for the individual patient, the absolute risk of a cardiovascular event up to their mid-40s is low," he said. "Patients should react in a similar way and not be too alarmed by our results." The 3,408 patients in the cohort study had been given growth hormone anytime from 1985 through 2010. Each was matched with 15 control patients using Sweden's national registry system. Two-thirds of the study participants were men. They were followed through the end of 2014, for a mean of 14.9 years. The underlying reason for the treatment did not make a big difference in the risk. Those who were diagnosed as small for gestational age faced a risk increased of 97%. The rate was 66% higher for patients considered to have isolated growth-hormone deficiency and 55% higher when the diagnosis was idiopathic short stature. Both growth-hormone deficiency and excess growth-hormone levels have been shown to increase the risk of cardiovascular problems. In the new study, Dr. Tidblad's team found that the longer the duration of growth hormone treatment, the greater the risk. It was not significantly elevated for two years of therapy, but double that of the control group when there were seven or more years of treatment. The total cumulative amount of growth hormone given was also significantly associated with higher risk. The adjusted hazard ratio for severe cardiovascular disease, including aneurysms, ischemic heart disease, cardiomyopathy, heart failure and cerebrovascular diseases, was 2.27 (95% confidence interval, 1.01 to 5.12). "We found that the highest risk was among those with the longest treatment duration and the highest cumulative dose, but with no association with the mean daily dose," the researchers write. "This finding could indicate a dose-response association but could also be caused by an underlying heterogeneity among the treated patients, wherein those with longest treatment duration and highest cumulative dose also had an underlying increased risk for the outcome for other reasons." "We will need to keep following previously treated patients and with time we will have more information regarding risks," said Dr. Tidblad. "With longer follow-up we will be able to say something about risk later in life and also have more events which will improve our statistical power for rare events." —Gene Emery Source
