390 - Off-Label but On the Rise: National Trends of Clonidine Use in U.S. NICUs, 2008–2022

Publication Number: 3377.390

Yasmeen A. Midgette, Duke University School of Medicine, Durham, NC, United States; Marianne Baquero, Duke Clinical Research Institute, Morrisville, NC, United States; Adhiti Parupalli, Duke Clinical Research Institute, Ellington, CT, United States; Lena A. Richardson, Duke Clinical Research Institute, Cary, NC, United States; Conrad M. Sharp, Duke University, Durham, NC, United States; Krish Vakani, Duke Clinical Research Institute, Raleigh, NC, United States; Melissa M. Campbell, Duke University Hospital, durham, NC, United States; Rachel G. Greenberg, Duke Clinical Research Institute, Durham, NC, United States; Daniel K. Benjamin, Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC, United States; Veeral Tolia, Pediatrix, Dallas, TX, United States; Ashley Stark, Comer Children's Hospital at University of Chicago Medical Center, Chicago, IL, United States

Background: Clonidine use in neonatal intensive care units (NICUs) has increased over time, with off-label use for sedation and neonatal abstinence syndrome (NAS), despite lacking approval by the Food and Drug Administration. Understanding trends in use of medications like clonidine is essential to inform pharmacologic care for infants.

Objective: To characterize clonidine prescribing patterns across US NICUs and evaluate associations with clinical characteristics, co-medication exposure, and clinical outcomes.

Design/Methods: We conducted a cohort study using the Pediatrix Clinical Data Warehouse from 2008 to 2022, including hospitalized, inborn infants ≥22 weeks gestational age (GA) and excluding infants transferred prior to discharge or with unknown disposition. Receipt of clonidine was defined as ≥1 day of use. Concomitant medication use and clinical outcomes were compared with Chi-square or Fisher's exact tests. Temporal trends were assessed using the Cochran-Armitage test.

Results: A total of 973,048 infants (Table 1) across 413 NICUs were included; with receipt of clonidine reported at least once at 80% (332/413) of sites (Figure 1A). The proportion of NICUs reporting clonidine use increased from 5% in 2008 to 53% in 2022 (Figure 1B). 3,220 (3%) infants received clonidine during hospitalization, and 609 (19%) of those infants were discharged on clonidine. The median GA for exposed infants was 36w (Q1, Q3: 33, 38w), and the median birth weight was 2.53 kg (1.91, 3.23 kg). Median duration of therapy was 16 days (Q1, Q3: 8, 29), postmenstrual age (PMA) at initiation was 39 weeks (Q1, Q3: 36, 45), and postnatal age (PNA) at initiation was 5 days (Q1, Q3: 1, 21), with later initiation in more premature infants. Among exposed infants, 88% also received opioids, 5% received benzodiazepines, and 6% received additional α-2 agonists. Infants exposed to clonidine had higher incidences of bronchopulmonary dysplasia, NAS, gastrostomy tube placement, and tracheostomy when compared to unexposed infants (all p < 0.001) (Table 2). Among clonidine-exposed infants, median length of stay was 78 days (Q1, Q3: 35-126) for those ≤25weeks GA and 5 days (Q1, Q3: 2-13) for those ≥37 weeks GA.

Conclusion(s): From 2008 to 2022, the percentage of infants receiving clonidine and the number of NICUs prescribing clonidine increased. These findings offer valuable insight into evolving off label prescribing practices in neonatal care and underscore the need for prospective studies to evaluate pharmacokinetics, dosing strategies, and long-term safety profile of clonidine in high-risk infants.

Table 1. Demographics of Study Population


Figure 1A and 1B. Trends in Clonidine use by infant and site percentage per year from 2008 to 2022
Figure 1A. Percentage of infants receiving clonidine by year from 2008 to 2022 rose significantly by year after 2012. Figure1B. Clonidine use in US NICUs rose from 3/413 sites (0.7%) in 2008 to (154/413) sites in 2022, with a significant uptrend (Cochran-Armitage test, p < 0.0001).

Table 2. Clinical Characteristics: Clonidine-Exposed vs Unexposed Infants
1 Bronchopulmonary dysplasia; BPD (Defined as respiratory support beyond 36 weeks PMA in infants <32 weeks GA, or ≥28 days of continuous support in those born at ≥32 weeks GA.)
2 Intraventricular Hemorrhage; IVH
3 Necrotizing Enterocolitis; NEC (Includes infants diagnosed with medical or surgical NEC)
4 Neonatal Abstinence Syndrome; NAS