Evidence Based Strategies: Neurodevelopmental Concerns in Children Undergoing Anesthesia

Anesthesia and sedation have become extraordinarily safe for children. Approximately 6 million children undergo anesthesia yearly for a variety of surgical and diagnostic procedures, with 25% of those being infants.¹ For the past decade, the issue of anesthesia-related neurotoxicity has been in the media spotlight ever since a 2016 Food and Drug Administration warning that “repeated or lengthy use of general anesthesia and sedation drugs during surgeries or procedures in children younger than three years of age...may affect the development of children’s brains.”² This warning was based on many in vitro and animal studies, while retrospective cohort human studies at the time resulted in less conclusive evidence.^3,4 In 2010, the Strategies for Mitigating Anesthesia-Related neuroToxicity in Tots (SmartTots) initiative was formed to facilitate research into this important question as well as provide educational tools for patients and medical professionals.

GAS, PANDA and MASK Studies

The General Anesthesia vs Spinal Anesthesia (GAS) study was an international, multi-site, randomized controlled trial to investigate the long-term neurodevelopmental outcomes of two commonly used modes of anesthesia—spinal and general. Newborns were randomly assigned to receive general or spinal anesthesia, then had developmental testing at ages 2 and 5 to determine whether there were neurocognitive differences between the groups. Evidence showed that general anesthesia in infancy does not cause measurable neurocognitive, behavioral or neurological deficits at 2 or 5 years of age compared with awake-regional anesthesia.⁶

The Pediatric Anesthesia and Neurodevelopment Assessment (PANDA) project was a large, multi-center study that examined two groups of children—those who had been exposed to a single episode of general anesthesia during inguinal hernia surgery before age 3 years and their siblings who had not been exposed—and assessed their neurodevelopment and cognitive functions between the ages of 8 and 15 years. Among healthy children with a single anesthesia exposure before age 36 months compared with healthy siblings with no anesthesia exposure, there were no statistically significant differences in IQ scores in later childhood.⁷

The Mayo Anesthesia Safety in Kids (MASK) study enrolled children less than 3 years of age who had either zero, one or multiple exposures to anesthesia. The authors concluded that exposure to a single anesthetic before the age of 3 was not associated with a decrease in intelligence or an increase in neurophysiological disorders, but those with multiple exposures had a “modest” decrease in speed and fine motor coordination.⁸

What to do when families ask about anesthesia safety

Most pediatric anesthesiologists have been asked the question, “Will anesthesia harm my child’s brain?” As the primary point of contact for many patients undergoing surgical and diagnostic procedures, pediatricians are increasingly faced with the same questions. Health care professionals should balance the benefits of anesthesia in children less than 3 years old, especially in procedures that may last longer than three hours or if multiple procedures are required. Consideration should be given to whether a diagnostic study requiring anesthesia in this age group will change clinical care.

So how should we counsel families who are concerned about neurotoxicity when a surgery or test is needed? There are a couple of key points. First, infants and children commonly require anesthesia for a variety of diagnostic tests and surgical procedures, and delaying those procedures or not providing adequate sedation/analgesia also comes with risks. Second, the most recent large-scale studies to date reassuringly show minimal or no impairment in neurocognitive development, especially for single short procedures. The SmartTots website (www.Smarttots.org) contains useful resources and reputable information for both families and health care professionals.

References:

1. Sun LS, Li G, DiMaggio CJ, et al. Feasibility and pilot study of the Pediatric Anesthesia NeuroDevelopment Assessment (PANDA) project. J Neurosurg Anesthesiol. 2012;24(4):382-388. doi:10.1097/ANA.0b013e31826a0371
2. FDA Drug Safety Communication: FDA review results in new warnings about using general anesthetics and sedation drugs in young children and pregnant women. US Food and Drug Administration. December 14th, 2016.
3. DiMaggio C, Sun LS, Kakavouli A, Byrne MW, Li G. A retrospective cohort study of the association of anesthesia and hernia repair surgery with behavioral and developmental disorders in young children. J Neurosurg Anesthesiol. 2009;21(4):286-291. doi:10.1097/ANA.0b013e3181a71f11
4. Kalkman CJ, Peelen L, Moons KG, et al. Behavior and development in children and age at the time of first anesthetic exposure. Anesthesiology. 2009;110(4):805-812. doi:10.1097/ALN.0b013e31819c7124
5. Borzage MT, Peterson BS. A scoping review of the mechanisms underlying developmental anesthetic neurotoxicity. Anesth Analg. 2025;140(2):409-426. doi:10.1213/ANE.0000000000006897
6. McCann ME, de Graff JC, Dorris L, et al. Neurodevelopmental outcome at 5 years of age after general anaesthesia or awake-regional anaesthesia in infancy (GAS): an international, multicentre, randomised, controlled equivalence trial. Lancet. 2019;393(10172):664-677. doi:10.1016/S0140-6736(18)32485-1
7. Sun LS, Li G, Miller TLK, et al. Association between a single general anesthesia exposure before age 36 months and neurocognitive outcomes in later childhood. JAMA. 2016;315(21):2312-2320. doi:10.1001/jama.2016.6967
8. Warner DO, Zaccariello MJ, Katusic SK, et al. Neuropsychological and behavioral outcomes after exposure of young children to procedures requiring general anesthesia: The Mayo Anesthesia Safety in Kids (MASK) Study. Anesthesiology. 2018;129(1):89-105. doi:10.1097/ALN.0000000000002232