Adolescent isotretinoin treatment for acne was not associated with clinically meaningful reductions in adult height in a nationwide Danish study of 379,196 people who underwent military conscription examinations.
The cross-sectional study, published online in JAMA Dermatology, included 368,338 men and 10,858 women who underwent Danish military conscription examinations from 2001 to 2015. Researchers linked conscription records with nationwide registry data to assess whether dispensed isotretinoin prescriptions prior to conscription were associated with adult height.
Adult height measured at conscription was the primary outcome. Researchers predefined a difference of at least 5 cm as clinically important. Analyses were adjusted for birth cohort year and educational level.
Compared with the reference group, which included conscripts without prescribed acne treatment or hospital-diagnosed acne, isotretinoin users had adjusted mean height differences of 0.3 cm among men and 0.3 cm among women. Both differences were below the predefined threshold for clinical relevance.
The researchers also evaluated patients who received long-term tetracycline-class antibiotics and topical acne therapies in addition to isotretinoin users and the no-acne reference group. These comparison groups helped address confounding by acne severity and health care use. Mean height varied minimally across acne treatment groups, including among patients receiving topical therapies, which served as a proxy for milder acne.
Among men, 16,739 had been dispensed isotretinoin prior to conscription. Among women, 278 had been dispensed isotretinoin. Mean height at age 19 years was 180 cm among men and 168 cm among women.
“Given the substantial psychosocial burden of moderate to severe acne, these findings may provide reassurance for clinicians, patients, and families and support shared evidence-based decision-making when isotretinoin therapy is considered during adolescence,” wrote lead study author Sigrun Alba Johannesdottir Schmidt, MD, of Aarhus University and Aarhus University Hospital, and colleagues.
The investigators also evaluated height by age at first isotretinoin prescription. Among male patients who initiated isotretinoin before age 13 years or at age 13 years, adjusted height differences were −1.7 cm and −1.8 cm, respectively. These estimates remained below the 5-cm threshold for clinical relevance, but the early-initiation groups were small, including 84 male patients who initiated treatment before age 13 years and 464 who initiated at age 13 years.
Among female patients, early-initiation estimates were especially imprecise. Only 7 female patients initiated isotretinoin before age 13 years, and 19 initiated at age 13 years. The female sample was also less population-representative than the male sample because women volunteered for conscription. Because peak height velocity occurs earlier among girls than boys, isotretinoin initiation after the period of greatest growth potential could also make the study less able to detect a growth effect among girls if treatment was started after peak height velocity.
Analyses of cumulative isotretinoin exposure showed no evidence of a dose-response association with adult height, including analyses restricted to exposure prior to age 15 years. Median cumulative isotretinoin dose was 5,000 mg among men and 4,750 mg among women.
The absence of a dose-response pattern was clinically relevant because concerns about isotretinoin and growth have centered on possible effects of retinoic acid on endochondral ossification through pathways involving fibroblast growth factors, bone morphogenetic proteins, and sonic hedgehog signaling. If isotretinoin impaired linear growth in a dose-dependent manner, a gradient by cumulative exposure might be expected.
As a secondary outcome, researchers evaluated stunting, defined as height at least 2 standard deviations below the population mean for age and sex. Among men, stunting occurred in 1.5% of isotretinoin users compared with 2.1% of the reference group. The researchers cautioned that this finding should not be interpreted as a protective effect of isotretinoin. Instead, they noted that a healthy-user effect or differences in health care access could partly explain both the slightly positive adjusted height difference and the lower prevalence of stunting among patients receiving dermatologist-prescribed isotretinoin.
The study used dispensed prescription data rather than issued prescriptions, and the researchers noted that patient co-payments increased confidence that medication exposure reflected actual use. Height was measured by medical staff at conscription rather than self-reported, strengthening outcome ascertainment.
Several sensitivity analyses yielded similar findings. These included analyses restricted to participants with complete prescription histories from age 11 years, analyses excluding patients with conditions or treatments that could affect growth, analyses using weight-adjusted cumulative dose, and analyses using a less stringent stunting threshold.
The researchers noted several limitations. The study was observational, and analyses beyond the prespecified primary hypothesis were exploratory. The study lacked repeated height measurements and information on pubertal timing, nutritional status, parental height, and weight at the time of prescription. Single-agent benzoyl peroxide is available without prescription in Denmark, so some patients with mild acne may have been included in the reference group.
The findings may not apply to high-dose isotretinoin regimens used in oncology or prolonged retinoid therapy for keratinization disorders, which differ from acne treatment in dose intensity, age at initiation, and concomitant therapies.
The study was funded by the Aage Bangs Foundation, Fonden til Lægevidenskabens Fremme, and the Health Research Foundation of Central Denmark Region. The funders had no role in the design or conduct of the study; collection, management, analysis, or interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication. Several researchers reported personal fees or grants outside the submitted work. John S. Barbieri, MD, of Brigham and Women’s Hospital, is an associate editor of JAMA Dermatology but was not involved in the review or acceptance of the manuscript. The researchers also reported using ChatGPT for language refinement during manuscript preparation, but not to generate data, analyses, or interpretations.
Source: JAMA Dermatology
