(45) Impact of Early Growth Trajectories and CFTR Modulator Therapy on Puberty in Cystic Fibrosis

Background: The advent of cystic fibrosis transmembrane conductance regulator (CFTR) modulators has led to a rapidly changing landscape in cystic fibrosis (CF) outcomes. It remains unclear to what degree puberty is affected in children with CF in this new era. Historically, children with CF experienced a 2-4-year delay in pubertal onset possibly as a manifestation of poor nutrition and/or CFTR dysfunction [1,2]. CFTR modulators have the potential to impact pubertal timing by improving nutritional status as well as normalizing CFTR function in the hypothalamic-pituitary-gonadal axis [3]. Pubertal progression in CF has not been explored in the era of CFTR modulators. Furthermore, the impact of early growth on puberty in CF is unknown.

Methods: Using national data from the US CF Foundation Patient Registry (CFFPR), this study aims to analyze associations between early growth trajectories and puberty using peak height velocity (PHV) as a proxy measure. PHV, or the “adolescent growth spurt,” describes the maximum rate of height increase for an individual. Age at PHV (APHV) is frequently used to approximate the timing of puberty. PHV and APHV will be derived using a shape invariant mixed model to approximate growth. Inclusion criteria are people ages 18 to 21 years between 2010 and 2019 with confirmed CF by sweat test or genotype analysis. We will classify early growth trajectories (0 to 6 years) based on weight-for-length (WFL) or body mass index (BMI) into mutually exclusive categories representing growth patterns that clinicians may seek to encourage (WFL-BMI always >50th percentile, increasing, or stable) or avoid (decreasing WFL-BMI). We will analyze the impact of early growth on APHV (primary endpoint) as well as actual PHV and final adult height (secondary endpoints).

We will perform unadjusted analyses using t-tests or analysis of variance. We will perform adjusted analyses using multivariable linear regression, including various potential confounders and effect modifiers. We will conduct stratified analyses based on sex and modulator use. We will also split analyses by birth cohort to evaluate if pubertal patterns have changed over time. Lastly, we will compare PHV, APHV, and adult height to published North American longitudinal standards to compare CF pubertal outcomes to the general population.

Results: We secured CFFPR data in late March 2022. Analyses are currently underway and are expected to be complete in two months. The dataset captures 12,615 people with CF. Regarding demographics, 52.5% are male. 91.9% are White, 5.2% are Black, 0.7% are Asian, and 2.2% are of another race. The median age at CF diagnosis was 0.5 years. Sixty-three percent are treated with CFTR modulator therapy, although the mean age at which therapy was prescribed is 21.7 years (after the completion of puberty). Approximately 14% (894 males and 830 females) were started on CFTR modulator therapy prior to age 18 years. The mean adult height is at the 36th percentile.

Conclusions: Conclusions are pending analytic results.

Acknowledgements: This work was supported by the Cystic Fibrosis Foundation [grant PATIL20B0].

References: [1] Sproul A, Huang N. Growth patterns in children with cystic fibrosis. J Pediatr. 1964;65(5):664-676.
[2] Aswani N, Taylor CJ, McGaw J, Pickering M, Rigby AS. Pubertal growth and development in cystic fibrosis: a retrospective review. Acta Paediatr. 2003;92(9):1029-1032.
[3] Goldsweig B, Kaminski B, Sidhaye A, Blackman SM, Kelly A. Puberty in cystic fibrosis. J Cyst Fibros. 2019;18:S88-S94.