Abstract
Background:
Isotretinoin is the first line treatment for severe acne, but its effects on adolescent growth remain unclear.
Objective:
To assess the effects of isotretinoin on final adult height and height velocity in adolescents treated for acne.
Methods:
This retrospective cohort study used the Rochester Epidemiology Project to identify patients diagnosed with acne between 2005–2021 who initiated isotretinoin or oral antibiotics before age 15. Height velocity was calculated using measurements taken within one year pre- and post-medication initiation, and final height was recorded at 18 years. Multivariable regression models adjusted for age and sex.
Results:
Among 226 isotretinoin-treated patients and 1,179 controls, final height did not differ significantly between groups (−0.67 cm; CI −2.21 to 0.87). However, isotretinoin-treated patients had a lower post-treatment height velocity (−0.12 cm/month; CI −0.21 to −0.04, p = 0.005) and a greater reduction in post- versus pre-treatment height velocity (−0.31 cm/month; CI −0.54 to −0.07, p = 0.011). No significant dosage effects were observed.
Limitations:
The study was limited by sample size, potential unmeasured confounders, and a predominantly non-Hispanic white population.
Conclusions:
While isotretinoin may reduce height velocity, it is not associated with negative effects on final adult height among adolescents treated for acne.
Keywords: isotretinoin, height, height velocity, acne, Rochester epidemiology project
Capsule summary
The effects of isotretinoin on adolescent growth remain unclear. This study suggests that while isotretinoin may temporarily reduce height velocity, it does not affect final adult height.
Clinicians can reassure patients and families that isotretinoin is unlikely to affect adult height, though temporary growth changes may occur.
Introduction
Isotretinoin is the first line treatment for severe acne and is considered the most effective medication for acne1. A labeled adverse effect of Accutane (isotretinoin) is premature epiphyseal closure2. Retinoic acid and its receptors are important modulators of multiple growth factor signaling pathways including fibroblast growth factors (FGF), bone morphogenic proteins (BMP), and sonic hedgehog protein (Shh), among others3.
Premature epiphyseal closure has been reported in case reports of children treated with high-dose isotretinoin for neuroblastoma,3–5 ichthyoses, and other disorders of cornification6. Proposed risk factors include higher doses of isotretinoin (e.g. 3–5mg/kg/day), longer duration of therapy (years), and younger age at treatment7. In a study of 20 children with high-risk neuroblastoma who were treated with isotretinoin and autologous stem cell transplantation (+/− radiation), survivors were significantly shorter as compared with matched healthy controls, with 11 out of the 20 children requiring growth hormone treatment8.
While premature epiphyseal closure has been sporadically reported in adolescents treated for acne with standard isotretinoin doses—both in case reports and post-marketing Food and Drug Administration (FDA) surveillance7—the overall impact of isotretinoin on adolescent height remains unclear. There is a need for rigorous studies to evaluate the potential effects of isotretinoin treatment for acne on adolescent growth and final adult height.
In this study, we conducted a retrospective, population-based analysis to assess final height and height velocity in adolescents treated with isotretinoin compared to acne controls who received oral antibiotics.
Methods
Patient selection
Patients with a diagnosis of acne (ICD codes L70.0, L70.5, L70.8, and L70.9) between January 1, 2005, and December 31, 2021, who were treated with at least three months of isotretinoin starting prior to the age of 15 years were identified using the Rochester Epidemiology Project (REP).
The REP is a unique, National Institutes of Health funded, records-linkage system that allows for population-based medical research in Olmsted County, Minnesota by linking all medical records of providers within the county into a single database. The REP captures comprehensive health data for all Olmsted County residents who receive care from Olmsted County health care providers such as Mayo Clinic, Olmsted Medical Center, and affiliated private practitioners. This system ensures continuous monitoring of healthcare information, even when patients switch providers of health systems within Olmsted County or move outside the county while continuing care with a REP-affiliated provider. By offering a county-wide, longitudinal data source, the REP enhances the validity and utility of epidemiologic studies9 by minimizing the risk of data loss due to patient migration.
The age of epiphyseal closure is varied but is shown to occur at 15–18-year age range in 90% of girls and at 17–20 range in 90% of boys10,11, as such, we restricted our population to those initiating therapy prior to age 15 to increase the likelihood that included individuals would be actively growing at the time they were receiving isotretinoin treatment. Follow-up data was collected through April 30, 2024, ensuring up-to-date information for each patient’s care timeline.
A comparator cohort was also established using the REP, consisting of patients with acne who were treated with oral antibiotics (including minocycline, tetracycline, doxycycline, erythromycin, and azithromycin) starting prior to the age of 15 years and not exposed to isotretinoin. This cohort was identified by matching up to ten individuals, based on sex and age at medication initiation, to each patient treated with isotretinoin.
Height measurements were obtained from vital signs recorded in patients’ charts during well-child visits or other routine appointments, with final height documented at age 18. Height velocity was calculated using any two height measurements taken less than 1 year before (pre-medication initiation velocity) or less than 1 year after (post-medication initiation velocity) the medication initiation date. Manual chart reviews were conducted to verify acne diagnoses and cumulative isotretinoin dosages to ensure data accuracy and consistency across all records.
Statistical analysis
The primary outcome of this study was final adult height in patients with acne who were treated with isotretinoin compared to those treated with oral antibiotics. Secondary outcomes included pre- and post- medication initiation height velocity and change in height velocity.
While the goal was to conduct fully matched analyses, due to heterogeneity in availability of height measurement data, unmatched analyses were used for the final cohort comparison. We adjusted for sex and age at medication initiation in our two groups using multivariable regression models to mitigate potential imbalances. Interaction terms between sex and age at medication initiation were assessed for all variables, and patients with missing data were excluded from analyses involving the respective variable. Additional covariates included medication dosage and duration.
Univariate comparisons between groups were made using the Kruskal-Wallis, Pearson Chi-Square or Fisher exact test, as appropriate. Multivariable analyses were performed using linear regression, adjusting for sex and age at medication initiation. Categorical variables were reported as numbers (percentage), and continuous variables were reported as medians (25th through 75th interquartile range) or means (standard deviation).
Statistical significance was defined as P value less than 0.05. Based on an a priori power calculation, a sample size of 142 per group was required to achieve 80% power to detect a one-inch (2.54 cm) difference in height, while 36 per group was needed to detect a two-inch (5.08 cm) difference. All statistical analyses were done using RStudio Version 4.1.3 (RStudio, PBC). This study is reported in accordance with the STROBE guidelines.
Results
We identified a total of 227 patients with acne treated with isotretinoin and a cohort of 1179 patients with acne treated with oral antibiotics, matched by sex and age at medication initiation. Patient demographics are reported in Table 1. The median age at treatment initiation was 14.25 years in the isotretinoin group and 14.76 years in the oral antibiotics group. Both groups consisted of 41% females and 59% males. The median cumulative dosage of isotretinoin was 163.06 mg/kg (IQR 144.05 to 205.07) and the median duration of therapy was 8.0 months (IQR 6.0 to 11.0).
Table 1:
Demographics of patients taking isotretinoin and oral antibiotics.
| Variable | Oral Antibiotic | Isotretinoin | Total |
|---|---|---|---|
| Number of patients (%) | 1179 | 227 | 1406 |
| Female | 480 (40.7) | 93 (41.0) | 573 (40.8) |
| Male | 699 (59.3) | 134 (59.0) | 833 (59.2) |
| Race (%) | |||
| American Indian or Alaska Native | 2 (0.2) | 0 | 2 (0.1) |
| Asian | 56 (4.8) | 7 (3.1) | 63 (4.5) |
| Black or African American | 41 (3.5) | 1 (0.4) | 42 (3.0) |
| Middle Eastern or North African | 4 (0.3) | 1 (0.4) | 5 (0.4) |
| Native Hawaiian or Pacific Islander | 2 (0.2) | 0 | 2 (0.1) |
| White | 999 (84.7) | 201 (88.6) | 1200 (85.4) |
| Mixed race/Other | 46 (3.9) | 6 (2.6) | 52 (3.7) |
| Unknown/Not reported | 29 (2.5) | 11 (4.9) | 40 (2.8) |
| Ethnicity (%) | |||
| Hispanic or Latino | 32 (2.7) | 5 (2.2) | 37 (2.6) |
| Not Hispanic or Latino | 967 (82.2) | 164 (72.3) | 1131 (80.6) |
| Unknown/Not reported | 178 (15.1) | 58 (25.6) | 236 (16.8) |
| Age at medication initiation, years (IQR1) | 14.76 (14.02, 15.40) | 14.25 (13.76, 14.67) | 14.65 (13.96, 15.30) |
| Cumulative dosage per weight, mg/kg (IQR1) | n/a | 163.06 (144.05, 205.07) | n/a |
| Length of time on medication, months (IQR1) | n/a | 8.0 (6.0, 11.0) | n/a |
Interquartile range
There were 179 patients (79.2%) treated with isotretinoin who reached the age of 18 by April 30, 2024. Among these patients, there were no significant differences in final height at 18 years between patients taking isotretinoin and those treated with oral antibiotics (173.60 cm vs. 175.54 cm, mean difference of −0.67 cm; 95% CI −2.21 to 0.87) (Table 2, Figure 1). Similar results were observed in stratified analyses by sex (Table 3).
Table 2:
Regression model for differences in height and height velocity between patients taking isotretinoin and oral antibiotics.
| Variable | Oral Antibiotic (SD1) | Isotretinoin (SD1) | Multivariate Coefficient2 (CI3) | P-value |
|---|---|---|---|---|
| Final height at 18 years, cm | 175.54 (10.16) | 173.60 (9.64) | −0.67 (−2.21, 0.87) | 0.392 |
| Pre-medication initiation height velocity4, cm/month | 0.37 (0.31) | 0.43 (0.34) | −0.01 (−0.09, 0.07) | 0.818 |
| Post-medication initiation height velocity5, cm/month | 0.34 (0.34) | 0.23 (0.17) | −0.12 (−0.21, −0.04) | 0.005 |
| Change in height velocity6, cm/month | 0.05 (0.33) | −0.28 (0.38) | −0.31 (−0.54, −0.07) | 0.011 |
Standard deviation.
Covariates included in model: sex, age at medication initiation.
95% confidence interval.
Taken by the difference in two measurements, 3–12 months apart before medication initiation, standardized to monthly.
Taken by the difference in two measurements, 3–12 months apart after medication initiation, standardized to monthly.
Average difference between post- and pre-medication initiation height velocity per individual.
Figure 1:
Differences in final height between patients taking isotretinoin and oral antibiotics.
The width of these violin plots at any point represents the density of data at that value—wider sections indicate more frequent values.
Table 3:
Variable stratification by sex and treatment group.
| Variable | Females (IQR7) | Males (IQR7) | Total (IQR7) |
|---|---|---|---|
| Age at medication initiation, years | |||
| Oral Antibiotic | 14.40 (13.53, 15.16) | 14.40 (13.53, 15.16) | 14.40 (13.53, 15.16) |
| Isotretinoin | 13.99 (13.52, 14.57) | 14.39 (13.95, 14.69) | 14.25 (13.76, 14.67) |
| Final height at 18 years, cm | |||
| Oral Antibiotic | 165.40 (161.00, 170.00) | 180.00 (174.00, 185.42) | 175.50 (168.37, 182.88) |
| Isotretinoin | 164.95 (160.04, 168.98) | 180.25 (175.10, 182.97) | 174.80 (166.72, 180.57) |
| Pre-medication initiation height velocity8, cm/month | |||
| Oral Antibiotic | 0.18 (0.10, 0.40) | 0.42 (0.24, 0.58) | 0.33 (0.16, 0.52) |
| Isotretinoin | 0.20 (0.09, 0.38) | 0.52 (0.30, 0.74) | 0.36 (0.15, 0.60) |
| Post-medication initiation height velocity9, cm/month | |||
| Oral Antibiotic | 0.21 (0.12, 0.33) | 0.35 (0.15, 0.56) | 0.25 (0.14, 0.44) |
| Isotretinoin | 0.13 (0.07, 0.28) | 0.24 (0.11, 0.36) | 0.19 (0.08, 0.34) |
| Change in height velocity10, cm/month | |||
| Oral Antibiotic | −0.08 (−0.15, −0.01) | 0.03 (−0.15, 0.24) | −0.03 (−0.16, 0.12) |
| Isotretinoin | 0.03 (−0.16, 0.06) | −0.65 (−0.68, −0.06) | −0.12 (−0.65, 0.05) |
Interquartile range
Taken by the difference in two measurements, 3–12 months apart before medication initiation, standardized to monthly.
Taken by the difference in two measurements, 3–12 months apart after medication initiation, standardized to monthly.
Average difference between post- and pre-medication initiation height velocity per individual.
In addition, we found no significant differences in final height among patients taking varying dosages of isotretinoin: <120 mg/kg (n = 24), 120–220 mg/kg (n = 155), >220 mg/kg (n = 48), although this analysis was limited by sample size. After adjusting for covariates, final height was not significantly different in either the <120 mg/kg group (p = 0.218) or the >220 mg/kg group (p = 0.370) compared to the 120–220 mg/kg group.
We identified a subset of patients with final height greater than 2 standard deviations below the mean, defined as a height cutoff of ≤163 cm (5’4”) for males and ≤151 cm (4’11”) for females12. There were 6 (1.28%) patients in the oral antibiotics group and 3 (2.34%) patients in the isotretinoin group who met this criterion (p = 0.383).
After adjusting for sex and age at medication initiation, patients taking isotretinoin had a significantly lower average monthly height velocity post-medication initiation compared to those treated with oral antibiotics (−0.12 cm/month, 95% CI −0.21 to −0.04, p = 0.005) (Table 2, Figure 2). In addition, there was a greater average reduction in height velocity comparing pre- versus post- medication initiation periods in patients taking isotretinoin compared with oral antibiotics (−0.31 cm/month, 95% CI −0.54 to −0.07, p = 0.011). The interaction terms between all variables were insignificant.
Figure 2:
Differences in post-medication initiation height velocity between patients taking isotretinoin and oral antibiotics.
The width of these violin plots at any point represents the density of data at that value—wider sections indicate more frequent values.
Discussion
We did not identify any statistically significant differences in final adult height between individuals treated with typical courses of isotretinoin and those treated with oral antibiotics for acne. Additionally, there was no greater incidence of short stature among isotretinoin-treated individuals compared to those treated with oral antibiotics. Our findings align with a cohort study by Cole and Shen, which found no decrease in adult height among patients aged 18 and under who were treated with isotretinoin compared to controls treated with doxycycline13. These findings provide reassurance that isotretinoin is unlikely to have a clinically significant impact on height.
There are several potential reasons that our findings may differ from prior case series describing premature epiphysial closure, particularly among those being treated for neuroblastoma and ichthyoses. Since these conditions often affect young children, the exposure may be much earlier and the duration of therapy may be much longer than what typically occurs for acne. Notably, in our study, the average age at medication initiation was closer to the time of epiphyseal closure, which may minimize potential effects on adolescents at peak growth velocity. In addition, the premature epiphyseal closure observed in those with neuroblastoma may have resulted from concurrent treatments such as radiation and stem cell transplantation rather than isotretinoin7,8. Furthermore, the lower daily and cumulative doses used for acne management—compared to conditions like neuroblastoma and ichthyoses—may be less likely to impact growth plate physiology. Although prior case reports have suggested that higher doses (e.g. >3–5 mg/kg/day) and longer duration (e.g. years) of therapy might be associated with greater risk of premature epiphyseal closure7, we did not identify any association between higher doses of isotretinoin therapy for acne and differences in height outcomes in the present study. Future research investigating isotretinoin initiation at earlier ages, higher cumulative doses, and with repeated courses would be valuable.
While we did find that that isotretinoin was associated with a decrease in height velocity, it is important to contextualize this finding in the setting of no observed differences in final adult height. Although we made efforts to account for age at medication initiation, the antibiotic cohort was slightly older at the initiation date than the isotretinoin group. This age difference may have placed the antibiotic group closer to peak height, resulting in slower natural growth and a smaller decline in height velocity (i.e. the antibiotic group may have been growing slower at the initiation date, which is supported by their slightly lower pre-medication initiation height velocity). Another possibility is that isotretinoin could induce a decrease in growth and height velocity during treatment, but the relatively transient nature of treatment for acne does not meaningfully affect final height. This finding is supported by observed transient suppression of biochemical markers of bone turnover and calcium homeostasis during isotretinoin therapy for acne, which returned to baseline within 14 days after treatment14. It is also possible that height velocity might increase after isotretinoin treatment cessation to compensate for any transient growth suppression, similar to what has been observed in some settings following systemic corticosteroid exposure15.
Overall, the findings of this study are reassuring for clinicians and parents concerned about the potential impact of isotretinoin on children’s growth. Currently, growth screening of adolescents is not recommended as part of the clinical evaluation for patients undergoing isotretinoin treatment for acne16. Our results provide further support for this practice to continue. These data can also provide valuable information for shared decision-making about whether to use isotretinoin for children who have not yet reached their final height.
Strengths and Limitations
Strengths of this study include the high-quality exposure and outcome data available in the REP, allowing for accurate assessment of final height and isotretinoin use, including cumulative dose. In addition, unlike prior work that included older adolescents who might already have achieved their final height, our study focused on a younger population to facilitate assessment of the effects of isotretinoin among adolescents who were likely to be actively growing.13
Our study is limited by the focused nature of the REP which tracks residents of Olmsted County, Minnesota. This patient population is largely non-Hispanic Caucasian and is less ethnically diverse than the entire US population, although there has been an influx of populations from around the world especially in younger age groups17. We also do not have information on timing of puberty, though we would not anticipate it to differ between the two groups. This study was also limited by sample size; while it was well powered to be able to detect one inch (2.54 cm) or greater difference in final height, we cannot exclude smaller potential effects on final height. Although a fully matched analysis would have provided greater synchronicity, our limited sample size and data regarding height measurements for each group prevented this from being achieved. Finally, given the observational nature of the study, there is the potential for unmeasured confounding variables, such as nutritional status and genetic predispositions, which could independently influence growth.
Conclusions
This study provides a population-based analysis of isotretinoin’s effect on height and height velocity. While our findings indicate that isotretinoin may be associated with a potential reduction in height velocity among adolescents treated for acne, no significant differences in final adult height were observed between the cohorts. These results suggest that isotretinoin is unlikely to have a clinically meaningful impact on final adult height in patients treated for acne. However, the risk of a potential negative effect on growth should be carefully considered for each individual patient as part of shared decision making. Future prospective studies are needed to further evaluate the potential effect of isotretinoin on height development.
Acknowledgements:
This study used the resources of the Rochester Epidemiology Project (REP) medical records-linkage system, which is supported by the National Institute on Aging (NIA; AG 058738), by the Mayo Clinic Research Committee, and by fees paid annually by REP users. The content of this article is solely the responsibility of the authors and does not represent the official views of the National Institutes of Health (NIH) or the Mayo Clinic.
Funding sources:
This publication was made possible by the Mayo Clinic CTSA through grant number UL1TR002377 from the National Center for Advancing Translational Sciences (NCATS), a component of the National Institutes of Health (NIH)
Footnotes
Conflicts of Interest: John S Barbieri has received consulting fees from Honeydew Care and Sanofi Pasteur for work unrelated to the present submission. The authors have no other conflicts of interest to declare.
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