Growth Hormone Treatment in Children Linked to Increased Cardiovascular Risk

Anders Tidblad, MD, PHD

Findings from a new study indicated that recombinant human growth hormone (rhGH) treatment in children is associated with increased risk of cardiovascular events in early adulthood, particularly in females.

However, the investigators noted causality remains indeterminable and absolute risk was low.

A team led by Anders Tidblad, MD, PhD, Division of Pediatric Endocrinology, Karolinska Institute, Sweden, conducted a nationwide population-based cohort study that accounted for children treated with rhGH from 1985 through 2010. Follow-up occurred through 2014.

Reasons for treatment included isolated growth hormone deficiency (GHD), small for gestational age (SGA), and idiopathic short stature (ISS).

“Concerns regarding long-term safety were raised in 2012 by a study of a French cohort of children treated previously with rhGH for GHD, SGA, and ISS, in which increased risks of overall cardiovascular mortality were reported; subsequent follow-up reported increased risk of cerebrovascular morbidity,” the team wrote.

Thus, there has long been a need to conduct robust long-term studies to corroborate these findings.

The Study

Tidblad and team matched each patient treated with rhGH with 15 individuals according to age, sex, and region. The control group was randomly selected from the overall population.

Using health care and population-based registers—such as the Swedish Naitonal GH Register for Children, rhGH clinical trials, and Swedish Total Population Register—the team gathered data on cardiovascular outcomes and covariates, which included gestational age, birth weight, birth length, socioeconomic status, and height.

They also collected information on mean growth hormone dose, duration of treatment, and cumulative dose.

The primary outcome was the first cardiovascular event recorded after the start of the follow-up period

The Results

A total of 3408 growth hormone-treated patients were included in the study—compared with 50,036 individuals in the control group. Of the entire study population (n = 53,444), 67.7% were men, and the mean age at study end was 25.1 years.

All patients were followed up for as long for 25 years, with a mean of follow-up of 14.9 years.

The team recorded as many as 1809 cardiovascular events. Of this amount, the crude incidence rate for rhGH patients was 25.6 events per 10,000 person-years—versus 22.6 events per 10,000 person-years in the control group.

The adjusted hazard ratio for all cardiovascular events was higher in patients than in the controls (HR, 1.69; 95% CI, 1.30-2.19).

This trend was also especially noted for women (HR, 2.05 95% CI, 1.31-3.20), when compared with men.

All subgroups of rhGH use were associated with cardiovascular risk as well. For example, SGA had a HR of 1.97 (95% CI, 1.28-3.04); GHD, 1.66 (95% CI, 1.21-2.26); and ISS, 1.55 (95% CI, 1.01-2.37).

Furthermore, higher risk for overall cardiovascular disease was linked with longer duration of rhGH treatment (HR, 2.08; 95% CI, 1.35-3.20) and total cumulative dose (HR, 2.0; 95% CI, 1.18-3.55).

And finally, the investigators reported that the adjusted HR for severe cardiovascular disease was 2.27 (95% CI, 1.01-5.12).

Conclusions

One particular limitation highlighted by Tidblad and colleagues was the possibility for confounding variables, such as the reason behind starting growth hormone treatment.

“We tried to handle such potential bias by applying a matched cohort study design, adjusting for multiple potential confounders, and performing dose-response analyses,” they wrote.

“However, it is impossible to completely avoid the possibility of residual confounding, and the associations described should be seen in this light and not be viewed as evidence of causal relationships.”

They indicated future studies of cardiovascular safety are needed to closely monitor such individuals, especially in female patients and those treated for SGA

The study, “Association of Childhood Growth Hormone Treatment With Long-term Cardiovascular Morbidity,” was published online in JAMA Pediatrics.