By Asja Kunøe
Chariman: Lone Graff Stensballe
Opponent: Liesbeth Duijts
Opponent: Lars Rejnmark
Glucocorticoids are potent drugs having anti-inflammatory, immunosuppressive and metabolic effects. Inhaled corticosteroid (ICS) is the preferred controller therapy for management of asthma in child ren but they have potential side effects. Side effects from ICS have primarily been related to the risk of a decrease in linear growth and impairment of bone mineralization due to suppression of the hypothalamic–pituitary–adrenal axis, but other potential side effects such as altered BMI development and body fat accumulation have more rarely been investigated. Results from studies in the field have been conflicting and evidence on the effect of long-term treatment, over a period of several years, is sparse, particularly in the young children. Young children may be particularly at risk of side effects because they are in a vulnerable phase of life with faster growth rates in infancy and early childhood. One complicating factor is that the asthma pathology itself may impair growth and the causal relationship of the associations are to be considered.
The aim of this PhD was to investigate the association between treatment with inhaled corticosteroid in the first 6 years of life on early childhood growth and body composition at age 6 years. Both studies in this PhD are based on data from two mother-child cohorts: Copenhagen Prospective Studies on Asthma in Childhood2000 (COPSAC2000) and COPSAC2010, where use of all ICS was registered prospectively from birth, adherence carefully evaluated, and treatment with ICS was conducted according to predefined algorithms.
In paper I, we investigated the association between standard ICS treatment in the first 6 years of life on height and bone mineral content (BMC) at age 6 years. We used the cumulative ICS dose as exposure and data from height measurements and measurements of bone composition from dual-energy X-ray absorptiometry (DXA) scans as outcome. We found an inverse association between ICS exposure during the first 6 years of life and height by age 6 years, but only in children with current ICS use in their 6th year of life. We found no association between ICS use and bone mineral content at age 6 years. In the future, the height development of the subgroup of children with continued use of ICS should be explored into adulthood.
In paper II, we investigated the association between standard ICS treatment in the first 6 years of life on BMI, age at adiposity rebound, body composition and blood lipids levels at age 6 years. We used the cumulative ICS dose as exposure and data from height and weight measurements to examine BMI z scores and age at adiposity rebound. Data from DXA scans was used to examine soft DXA measurement and serum samples were used to examine blood lipid profiles. We found an increased BMI z score; an earlier age at adiposity rebound and a trend of an increased android body fat percentage at age 6 years. We found young children starting asthma treatment having increased risk of additional weight gain at age 6 years, particularly treatment between age 3 and 6 years. We did not find a “dose-response” relationship with a stronger effect in those children with the highest cumulative dose/longest duration of treatment. No associations between ICS exposure and blood lipids were found. In the future, the causal relationship behind the association between ICS and higher BMI, earlier age at adiposity rebound and a trend of increased android body fat percentage at age 6 years should be addressed.
In conclusion, our findings show that long-term treatment with ICS in young children 0 to 6 years of age is associated with potential side effects in relation to height, BMI, age at adiposity rebound and android body fat. We found catch up height after one-year discontinuation of treatment. The higher BMI and trend towards higher android fat percentage at age 6 years and earlier age of adiposity, did not disappear after cessation of treatment. The causal mechanisms and direction remain unclear.
Our findings add to the field of potential side effects from treatment with ICS in relation to early childhood growth and body composition, which has rarely been studied in such young age group. This knowledge is important information for parents and stress the importance of promoting a healthy lifestyle in young children with asthma.