Version May 2024
INTRODUCTION — The possibility that anesthetic and sedative drugs may be neurotoxic to the developing brain is of widespread importance to patients, parents, and the clinicians who care for them. This topic will discuss the animal studies that initially questioned the safety of anesthetics on the developing brain, the proposed mechanisms of damage, as well as the clinical studies and the limitations of studies in humans.
THE ISSUE — Studies in animals have shown that anesthetic and sedative drugs can cause neuronal damage to the developing brain, resulting in lasting behavioral and cognitive deficits. Some human studies also suggest an association between exposure to anesthesia in early childhood and subsequent neurodevelopmental deficit, but causation has not been established, and specific anesthetic and patient factors that may affect risk remain unclear [1].
Any degree of neurotoxicity of anesthetic and sedative drugs in humans may have widespread implications. In the United States, over 1.3 million children under the age of five years undergo surgical procedures each year [2,3]. Most of these children require anesthesia to tolerate these procedures, and most of these procedures cannot be delayed without adding substantial surgical risk. In addition, an increasing number of young children receive sedatives or general anesthesia for neuroimaging studies [4], with many more requiring procedural sedation in the emergency department.
In 2016, the US Food and Drug Administration (FDA) issued a warning about potential risks of negative effects on the developing brain from administration of anesthetics for children under age three, as well as pregnant women during their third trimester, especially for repeated exposures or procedures lasting more than three hours (see 'The FDA warning' below). Most children who undergo general anesthesia are exposed for less than the FDA defined high-risk threshold of three hours. In a retrospective cohort analysis of approximately 1.5 million pediatric (<18 years of age) anesthetic billing records from the National Anesthesia Clinical Outcomes Registry, the median anesthetic duration was 57 minutes, with 6 percent of anesthetics lasting longer than three hours, but in children under one year old, 13.7 percent of anesthetics lasted longer than three hours [5]. In another retrospective study of approximately 21,000 children born between 1994 and 2007 in Minnesota, 14.9 percent of children were exposed to anesthesia before three years of age. Of the children exposed to anesthesia, 26.3 percent had either one exposure longer than three hours or multiple anesthetic exposures [6].
PROPOSED MECHANISMS — Much of the research on the mechanisms of anesthetic neurotoxicity has focused on apoptosis, though there is evidence that other mechanisms may be involved.
●Oxidative stress associated apoptosis – Anesthetic agents cause neuronal oxidative stress by inducing reactive oxygen species (ROS) formation within mitochondria during exposure [7,8]. ROS produced in this setting permits cytochrome c mobilization from the inner mitochondrial membrane [9,10]. Simultaneously, the outer mitochondrial membrane becomes permeable following anesthetic-mediated gamma-aminobutyric acidA (GABAA) receptor stimulation and N-methyl-D-aspartate (NMDA) receptor antagonism [11]. The combination of these events allows cytochrome c to be released into the cytosol and sets in motion a cascade of cellular events that ultimately leads to apoptotic neuronal cell death.
●Other mechanisms – Laboratory studies involving human embryonic stem cells and rodent neurons have suggested that anesthetics may impair neural development during critical periods through abnormalities of NMDA and/or GABA receptor expression, activity, and signaling; neuroinflammation; and dysregulation of other growth and survival pathways [7,10-16]. Furthermore, other downstream developmental processes, such as synaptogenesis, neurogenesis, and dendritic branching, may be targeted and disrupted.
NEUROTOXICOLOGIC EFFECTS IN ANIMAL STUDIES — Animal studies in multiple species from worms to nonhuman primates have reported neuronal apoptosis, and some studies have reported behavioral changes associated with exposure to anesthetics [17-19]. In contrast, a handful of preclinical studies failed to identify deleterious neurobehavioral effects of anesthetics [17]. Virtually all of the commonly used anesthetic agents (eg, propofol, midazolam, nitrous oxide, isoflurane) have been shown to elicit a degree of a neurotoxicologic response in some studies.
Rodent studies — An initial study on anesthetic neurotoxicity reported that exposure of immature rodents to a combination of commonly used anesthetic agents (ie, midazolam, nitrous oxide, and isoflurane) resulted in deletion of neurons, defects in synaptic function in the hippocampus, and cognitive impairment as juveniles and young adults [20]. Subsequent studies have corroborated these findings in both mice and rats, using a variety of anesthetic agents, durations of exposure, and a range of outcome measures [21].
Translation of the results of rodent studies to humans is limited by a number of factors, including the following:
●Most importantly, the greater complexity of the human brain and longer period of development in humans may result in a greater capacity for neuroplasticity and recovery from any insult.
●The differential timing and rate of brain maturation across species. (See 'Vulnerable age periods' below.)
●Dose and duration of anesthesia in animal studies that often exceed clinically relevant equivalents in humans.
●Difficulty monitoring physiologic parameters in rodents (eg, hypoxia, hypercarbia) that could affect neurologic outcome.
Nonhuman primate studies — Several studies have reported that both single and multiple exposures to anesthetic agents in nonhuman primates (NHPs) result in long term neurodevelopmental defects. The duration of a single exposure was as long as 24 hours. These studies are likely of greater translational value than rodent studies because the neurodevelopmental stage of NHPs is similar to humans at birth. In addition, in contrast with rodent studies, the conditions of human anesthesia can be mimicked in NHPs, and physiologic parameters can be measured and homeostasis maintained during anesthesia, as they would be in humans.
●In one study, infant rhesus monkeys that were exposed to sevoflurane for four hours on days of life 6 to 10, followed by subsequent exposures on days of life 14 and 28, demonstrated increased anxiety compared with controls that underwent only a brief period of maternal separation [22]. Anxiety was measured with the human intruder task, a standardized tool that allows assessment of emotional reactivity.
●In another study, infant rhesus macaques that were exposed to isoflurane for five hours on days of life 6, 9, and 12 demonstrated motor reflex deficits at one month of age and increased anxiety at 12 months of age [23]. Importantly, there were no significant effects of a single isoflurane exposure in this cohort.
●Studies have reported neuronal apoptosis in the fetal and neonatal NHP brain induced by prolonged exposure (5 to 24 hours) to isoflurane [24-26], ketamine [27-29], or propofol [30]. In one study, an increase in astrocyte activation was found in these same brain regions two years after a five hour neonatal exposure to isoflurane [31].
●In a post hoc analysis of imaging data obtained in NHPs at either 12 or 18 months of age, repeated exposure to ketamine or isoflurane was associated with widespread reduction in white matter integrity [32]. There were no evaluations to assess the functional effects of these changes, or long-term follow-up for potential resolution. This study does suggest that anesthesia-related brain changes may be detectable in vivo using noninvasive imaging.
Translation of the results of NHP studies to humans is limited by several factors:
●Assessment of neurodevelopmental outcome in other animal species cannot address the complexity of higher-order cognitive function in children [33-36].
●Controlled experimental exposure of animals to anesthesia does not model or account for the confounding indications for surgery and anesthesia exposure known to occur in infants and children. While studies in humans almost universally evaluate anesthetic exposure associated with surgery, the surgical exposure and any resulting inflammation is not typically addressed in animal models of anesthetic exposure.
●The prolonged administration of anesthetics used in some of these studies may not be relevant for many common procedures in humans.
●It has not been possible to prove that anesthesia-induced neuronal cell death or other histopathology actually occurs in humans, since histologic assessment cannot be performed on the brains of relatively healthy children after exposure to anesthesia [33].
LACK OF DEFINITIVE EVIDENCE IN HUMAN STUDIES — While animal studies find neurotoxic effects due to anesthetic medications, human studies have produced mixed results and have important limitations. Specifically, in most clinical studies it is difficult to distinguish the effect of the anesthetic medication from other patient and peri-operative factors. As a result, the question of whether anesthesia has any long-term neurodevelopmental effects on young children remains unclear. The best evidence suggests that exposure to anesthesia has limited to no association with detrimental effects on intelligence. However, a number of questions still remain, particularly the association between anesthesia exposure and other neurodevelopmental outcomes such as behavior, the effect of prolonged or multiple exposures, and the impact on potentially vulnerable patient populations.
Limitations of the literature — There has only been one published randomized clinical trial (see 'Prospective, randomized trial' below). All remaining clinical studies are observational studies, with the following limitations:
●The major limitation of the observational studies is the inability to determine whether an observed detrimental effect is due to the anesthesia or other factors such as the surgery or underlying medical condition.
●Existing studies use a variety of outcome measures, with variable sensitivity for assessment of anesthetic effects.
●Existing studies have involved varied timing of exposure to anesthesia and neurodevelopmental assessment of the children.
●In most studies, there is heterogeneous or unknown anesthetic drug administration.
●Many studies are limited to children in one geographic area or institution.
Prospective, randomized trial — The General Anaesthesia compared to Spinal anaesthesia (GAS) trial is an international assessor-masked randomized controlled trial and is the only published randomized controlled trial evaluating anesthetic neurotoxicity in children [37]. The results suggest that a brief exposure to sevoflurane anesthesia in early infancy does not affect neurodevelopmental outcome at age five years.
The GAS trial is an international study of infants undergoing inguinal hernia repair in which 363 infants were randomly assigned to receive a short pure sevoflurane general anesthetic with a median duration of exposure of 54 minutes, and 359 infants to awake regional anesthesia (spinal and/or caudal) [37]. The primary outcome (the Wechsler Preschool and Primary Scale of Intelligence Third Edition Full Scale Intelligence Score [FSIQ] at age five years) was similar between groups. The mean FSIQ score was 99.1 in the awake regional anesthesia group, versus 99 in the general anesthesia group, mean difference 0.2 (95% CI -2.6 to 3.1). The majority of secondary behavioral and neurocognitive outcomes were also similar between groups.
The results of the randomized controlled GAS trial may not be generalizable to children who undergo prolonged anesthesia, or who receive multiple anesthetic agents. In addition, 84 percent of the infants in the GAS trial were male, and it is unknown whether sex affects neurotoxicity.
Observational studies — Some retrospective observational studies have reported an association between anesthesia exposure early in life and the development of adverse neurodevelopmental outcomes, other studies have reported an association only with multiple rather than single exposures, and still others have reported no such association. However, significant heterogeneity exists between studies, including the outcomes that were assessed, the patient populations evaluated, the types of surgical procedures performed, and the ages in which the children were exposed. Some representative studies are discussed here, according to the outcome measure that was tested. In some studies, multiple outcomes were measured.
●Academic and teacher evaluation – A number of studies have used population wide educational databases to evaluate academic achievement testing and teacher ratings in children exposed to anesthesia. Most studies evaluating academic achievement or teacher evaluation in children exposed to anesthesia have reported either no difference or a marginal decrease compared with unexposed children.
A limitation of these studies is that academic achievement testing and teacher evaluations may be an insensitive measure of the effects of anesthesia. In studies in which multiple parameters were evaluated, there has been no difference in academic test results between study groups, whereas neuropsychologic testing showed an effect of anesthesia [38]. It should be noted that academic achievement tests often vary among states in the United States and among countries in the world.
Representative studies are discussed here.
•In three studies from Canada, the results of the early developmental index (EDI), a standardized developmental assessment teacher questionnaire evaluating five to six year olds across Canada, were compared for children who had surgery and anesthesia and those who had not.
-In one of these studies, approximately 28,400 children from Ontario who had surgery before school age were matched with approximately 56,000 children with no anesthesia exposure. Children who had surgery had a statistically significant but small increased risk of early developmental vulnerability (adjusted odds ratio [aOR] 1.05, 95% CI 1.01-1.08), defined as scoring below the 10th percentile in any one domain in the EDI [39].
-Another study from Manitoba that included 4470 children who had surgery before age four years also reported a statistically significant but small decrease in EDI scores in children who had anesthesia, compared with unexposed children [40].
-In a retrospective sibling-matched cohort study that included 2346 sibling pairs with only one child in the pair who underwent surgery prior to testing at age five or six years, there were no differences in early developmental vulnerability (aOR 1.14, 95% CI 0.98-1.33) or scores in any of the major EDI domains [41].
•In a study from Sweden, 33,514 children with a single anesthetic exposure before age four years had academic achievement scores that were statistically lower than unexposed children but the difference was small [42]. In a subset of 9198 boys in this study who also took an IQ test for military enlistment, slightly lower scores were found in exposed compared with unexposed boys.
•In a study of children from Minnesota, 350 children exposed to anesthesia for surgery before age two years were no different from unexposed children in the majority of group-administered academic achievement test outcomes [43]. However, children with multiple anesthetic exposures had a higher risk when learning disability was used as an outcome measure (hazard ratio [HR] 2.12, 95% CI 1.26-3.54). Children with a single instance of anesthetic exposure were not significantly different from unexposed children using either outcome.
•Another study used data from the Western Australian Pregnancy Cohort (Raine) study to evaluate academic achievement, ICD-9 coded clinical diagnosis, and directly assessed neuropsychologic testing at age 10 years, in 781 children, 112 of whom had anesthesia before three years of age [38]. Children exposed to anesthesia were at increased risk for deficits as measured by direct neuropsychologic testing and ICD-9 coded language and cognitive disorders, but there was no difference in academic achievement scores.
●Learning disability – Development of learning disability has been associated with exposure to anesthesia and surgery, particularly with multiple exposures. Learning disability is defined as a combination of academic achievement and IQ testing [44].
•In one population-based, retrospective birth cohort study that included 5357 children from Minnesota born between 1976 and 1982, the 593 children who received general anesthesia for surgery before age four years had an increased risk of learning disability with two anesthetics (HR 1.59, 95% CI 1.06-2.37) and three or more anesthetics (HR 2.60, 95% CI 1.60-4.24), but no difference was found with a single exposure to anesthesia [45]. This study was repeated with 1057 children from Minnesota born between 1996 and 2000, which also found an increased risk of learning disability in children with two or more exposures (HR 2.17, 95% CI 1.32-3.59), but no increased risk in children who had a single exposure [46].
•A subsequent analysis of the children from the same birth cohort who received anesthesia before the age of two years reported an approximately twofold increase in development of learning disabilities in children with multiple, but not single, exposures to anesthesia [43].
●Developmental and psychiatric disorders – Exposure to surgery and anesthesia at a young age has been associated with an increased risk of subsequent clinical diagnoses for psychiatric and developmental disorders. In some studies, increased risk was associated only with multiple anesthesia exposures, while other studies have reported such an association with a single exposure.
•In a study involving a cohort of 383 exposed children enrolled in New York State Medicaid, children exposed under the age of three years for inguinal hernia repair had an increased risk of an ICD-9 coded diagnosis for developmental delay or behavioral disorder (HR 2.3, 95% CI 1.3-4.1) [47]. In a second study of 304 exposed children among 10,450 siblings in the New York State Medicaid cohort, children exposed under age three years for any surgical procedure also had an increased risk of ICD-9 coded diagnoses for developmental delay or behavioral disorder (HR 1.6, 95% CI 1.4-1.8), compared with unexposed siblings [48].
•In a study of 350 children from Minnesota exposed to anesthesia before age two years, those with multiple exposures were found to have an increased risk of a clinical diagnosis for attention deficit hyperactivity disorder (HR 1.95 95% CI 1.03-3.71), while no increased risk was found with a single exposure [49].
•In a study of children enrolled in Medicaid in New York and Texas, 42,687 children with a single exposure to anesthesia for a common pediatric procedure before five years of age were compared to propensity score matched children who did not have surgery and anesthesia [50]. Compared with unexposed children, those exposed to surgery and anesthesia were 37 percent more likely to subsequently use attention deficit hyperactivity disorder (ADHD) medication (HR 1.37, 95% CI 1.3-1.44).
•In a study of children with commercial medical insurance, 30,251 singly exposed children, 16,228 multiply exposed children, and 138,523 unexposed children were evaluated [51]. Compared with unexposed children, those with a single exposure had a 39 percent increased risk of ADHD diagnosis (HR 1.39, 95% CI 1.32-1.47), and those with multiple exposures had a 75 percent increased risk (HR 1.75, 95% CI 1.62-1.87).
●Neuropsychologic assessments and parental reports of behavior – Of the studies using neuropsychologic assessments and reports of behavior by parents as outcome measures, several have found a difference in specific neurodevelopmental domains, while one study found no differences in any domain. The one negative study involved healthy children undergoing a relatively minor procedure.
•The Pediatric Anesthesia Neurodevelopment Assessment (PANDA) study compared intelligence quotient (IQ) scores, neurocognitive function, and behavior at age 8 to 15 years, in 105 sibling pairs in which only one sibling had a single exposure to anesthesia for inguinal hernia repair before age 36 months [52]. The sibling cohort design minimized confounders (eg, genetics, parental education level, and socioeconomic factors). There was no difference between exposed and unexposed siblings in IQ or neurodevelopmental domains including language, executive function, or memory.
•In a study of 321 children exposed to anesthesia before age three, exposed children were found to have increased deficits in receptive language (adjusted risk ratio [aRR] 1.87, 95% CI 1.20-2.93), expressive language (aRR 1.72, 95% CI 1.12-2.64), and abstract reasoning (aRR 1.69, 95% CI 1.13-2.53) at age 10 [53]. Not all cognitive domains were affected, however, and no differences were seen in behavior surveys or motor function.
•In the Mayo Anesthesia Safety in Kids (MASK) matched cohort study, 997 children who had no anesthesia, a single exposure to general anesthesia, or multiple exposures prior to age three, were tested for general intelligence and neuropsychologic domains [54]; 380 children had one anesthetic, 206 children had multiple anesthetics, and 411 had no anesthesia. There was no difference in intelligence quotient (IQ) among groups. Multiple anesthetic exposures were associated with modest decreases in processing speed, fine motor coordination, and increased parent-reported behavioral problems compared with unexposed children. Parents also reported more difficulty with executive function and reading in both singly- and multiply-exposed children.
•In a prospective cohort study including 644 healthy infants, 238 of whom who underwent minor surgery prior to 15 months of age, there were no differences in cognitive, language, motor or socioemotional parameters at 24 months of age between children exposed to anesthesia versus unexposed [55]. However, in exposed children differences in infant behavior and neurophysiology were found at 6 and 18 months, and parent reported behavior scores were poorer at 24 months.
•The Avon Longitudinal Study of Parents and Children (ALSPAC), a birth cohort from England, evaluated 13,433 children using a wide array of neurodevelopmental assessments at various ages [56]. In the cohort, 1110 children had a single exposure and 212 had multiple exposures to surgery and anesthesia. Compared to children unexposed before age four years, those with single and multiple exposures had lower scores in social communication at age nine years old, and motor function, specifically manual dexterity at age seven years old. Children with multiple exposures also had lower scores in dynamic balance at seven years and an increased number of behavioral difficulties at age eight years. Differences were not seen in a number of other outcomes including general cognitive ability, attention, memory, language, and academic achievement.
Meta-analyses — A number of different meta-analyses have been performed synthesizing data from the published clinical studies. Meta-analyses that have pooled data from wide ranges of different outcomes have found that neurodevelopmental outcomes are generally worse in children exposed to surgery and anesthesia than those who have not required surgery and anesthesia. Results from these studies are difficult to interpret given the heterogeneity in the included studies and outcomes. In an attempt to address the issue of heterogeneity, some meta-analyses only pooled similar outcomes and reported that while significantly worse scores were seen in some outcomes such as behavioral problems, a limited association was seen in others like intelligence. Meta-analyses however do not mitigate the fundamental limitations of potential bias and confounding inherent to all observational studies.
●Several meta-analyses have evaluated the association between early anesthetic exposures and subsequent neurodevelopmental outcomes using the earlier published studies, and all have found an association between anesthetic exposure and adverse neurodevelopmental outcome [57-59]. However, these studies should be interpreted with caution; all neurodevelopmental outcomes may not be equivalent, yet all types of outcomes were combined in these studies. These meta-analyses did not include the more recent studies of large academic achievement databases as well as prospective studies in which most of the outcomes assessed were similar in exposed and unexposed children.
●A 2021 meta-analysis combined data from 1644 children evaluated in prospective studies and compared common outcomes between studies [60]. No differences were found in IQ. While parent-reported externalizing, internalizing, and total behavioral scores were numerically worse in the exposed compared with unexposed children, the scores were within normal range for both exposed and unexposed.
●A 2022 meta-analysis combined data from 31 studies evaluating 13 different neurodevelopmental domains [61]. The numbers of children assessed within each domain ranged from 571 to 63,315 exposed and 802 to 311,610 unexposed children. Childhood exposure to general anesthesia was associated with poorer outcomes in the number of neurodevelopmental domains with the strongest associations found in behavioral problems and neurodevelopmental disorder diagnoses, as well as in executive function, nonverbal reasoning, motor function, and, to a lesser extent, language, general development, and academics. Cognition score differences had the weakest association.
VULNERABLE AGE PERIODS — The age at which the developing human brain may be most vulnerable to neurotoxic effects of anesthetic drugs is unknown, and is controversial. There is little support for delaying necessary minor surgery in young children to reduce neurodevelopmental risks.
Whereas brain development extends from the embryonic period until and through adolescence, neurodevelopment may be more susceptible to environmental insult during specific periods depending on the toxicant [62]. In rodent studies, the vulnerable period to anesthesia is thought to correspond to the period of maximal synaptogenesis (ie, approximately two days before birth until two weeks after birth) [63], based solely on findings of induced apoptosis and neurodegeneration during this time period [21,64,65]. Translation of this data to humans are debated as synaptogenesis in children peaks at under six months of age in the sensorimotor cortex, at approximately 10 months of age in the parietal and temporal cortices, and at approximately age three years in the prefrontal cortex [66].
Studies on neurotoxicity have involved children exposed to anesthesia from as early as birth to as late as 10 years of age. While some studies have found varying risk of neurodevelopmental deficit based on the age at exposure to anesthesia, most have not accounted for the fact that children tend to receive different procedures at different ages.
●In one study, children exposed to anesthesia before age three had an increased risk of deficits in language and reasoning, but the same deficits were not present in children exposed between ages three and five, and 5 and 10, suggesting a potential vulnerability at a younger age [67].
●The opposite result, however, was found in one of the studies from Canada, finding that children exposed between ages two and four years were more likely to have deficits than children exposed from age zero to two years, suggesting vulnerability at an older age [40]. In this study, however, the majority of children exposed at ages two to four years received anesthesia for dental procedures. It is possible that children who require anesthesia for dental procedures have a higher incidence of underlying behavioral problems compared with children who do not require anesthesia for these procedures.
●One other large retrospective study compared the risk of a mental health diagnosis or developmental delay for children in eleven separate age cohorts (from <28 weeks to 5 years) undergoing minor common surgical procedures with matched controls [68]. Although there was an increased risk for a mental health disorder, developmental delay, or attention deficit hyperactivity disorder (ADHD), in children with anesthesia exposure (HRs 1.26 to 1.31), there was no difference in risk between the different age cohorts.
PRENATAL EXPOSURE TO ANESTHESIA — Data on the neurotoxic effects of in utero exposure to anesthesia are limited. While some studies have reported associations between prenatal exposure to general anesthesia and worse neurodevelopmental scores, the studies are small and potential confounders may be present. Given the risk of complications to mothers and children, necessary surgery during pregnancy should not be avoided or delayed.
Fetal effects of anesthesia and surgery during pregnancy are discussed separately. (See "Anesthesia for nonobstetric surgery during pregnancy", section on 'Effects of anesthetics on the fetus and the pregnancy'.)
POTENTIALLY TOXIC EXPOSURE DOSES AND SPECIFIC DRUGS — The minimum potentially neurotoxic doses of sedatives and anesthetics in humans are unknown. While subanesthetic doses of propofol [69], ketamine, midazolam [70], and isoflurane [16] have been found to cause neuronal apoptosis in rodent brains, exposure to specific doses and agents has not been well studied in humans.
Most human studies evaluate exposures to general anesthesia but lack information on the specific drugs and doses administered, or even the duration of anesthesia exposure. Thus, the number of exposures to anesthesia has been used as a surrogate for dose, with a single exposure considered to be a lower dose, and multiple exposures a higher dose. However, this approach may not account for the fact that some children undergo single complex procedures with long exposures, while others undergo multiple short straightforward procedures. Whether the number of exposures has an effect independent of the total duration of anesthesia is also unknown.
●In the studies in Minnesota that used learning disability as an outcome, deficits have only been found in multiple exposures, but not single exposures [43,45,71].
●In studies of academic achievement, the association between exposure number and decreased neurodevelopmental function has been inconsistent [39,40,42].
Some studies have evaluated types of drugs and exposure doses. But since higher doses of and more exposures to anesthetic medications may be associated with higher levels of comorbid illness, conclusions from these studies may be limited by potential confounders, as discussed above. (See 'Limitations of the literature' above.)
●One retrospective observational study evaluated the effects of administration of specific anesthetic or sedative drugs to very preterm infants on subsequent full scale intelligence quotient (FSIQ) [72]. This study included 731 infants (gestational age <29 weeks and/or birth weight <1000 g) who were admitted to a neonatal ICU and received volatile anesthetics, propofol, benzodiazepines, ketamine, chloral hydrate, barbiturates and/or opioids up to a post-conceptual age of 45 weeks. Administration of all drugs other than opioids was associated with 3 to 4 point average reduction in FSIQ at 36 months corrected age, with no association between opioid administration and any changes in FSIQ.
●Another retrospective study evaluated the cumulative sedative and anesthetic doses and subsequent neurodevelopmental outcomes in a cohort of 110 infants with surgery for congenital heart disease [73]. There was no association between the dose of volatile anesthetic agents, opioids, benzodiazepines and dexmedetomidine on motor, cognitive, and language scores at 18 months of age. However, higher ketamine doses were associated with poorer motor performance.
THE FDA WARNING — Based on the published animal and clinical studies, as well as input from neurotoxicity investigators and stakeholders, in December 2016, the US Food and Drug Administration (FDA) announced warnings about potential risks of negative effects on the developing brain from administration of anesthetics and sedative drugs to pregnant women and children under age three, as well as pregnant women during their third trimester, especially for repeated exposures or procedures lasting more than three hours [74]. The FDA recommends that health care providers discuss with pregnant patients and parents of young children the benefits, risks, and appropriate timing of surgery requiring anesthesia that will take longer than three hours. However, the degree of risk remains unclear. The statements in the FDA warning that the children at risk are those who are under three years or in utero, and are exposed for more than three hours, are largely based on animal data and need to be further verified in clinical studies. Due to the lack of clinical evidence, in April 2017, the FDA modified their warning, stating that medically necessary procedures in pregnant women and children under age three should not be delayed and that practitioners should follow their usual practice paradigms [75].
In response to the FDA warning both the Society for Pediatric Anesthesia (SPA) [76] and the American College of Obstetrics and Gynecology (ACOG) [77] responded with statements of concern that necessary surgery and procedures requiring anesthesia might be delayed or avoided because of uncertain risks of deleterious effects of anesthesia.
WHAT WE TELL PARENTS AND PATIENTS — When asked about the risks of anesthesia by parents, patients, and care providers, clinicians should state that while children who need surgery and anesthesia have worse scores in some neurodevelopmental outcomes compared with children who do not need surgery and anesthesia, these differences cannot yet be attributed to anesthesia exposure, and there is still uncertainty that exposure to anesthesia has any lasting effects in children or fetuses [78].
Some institutions and clinicians have elected to routinely include discussion of the potential risks of neurotoxicity of anesthetics as part of informed consent [79] and there are resources available for those interested in doing so, including information on the website for the Society for Pediatric Anesthesia.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Pediatric anesthesia".)
SUMMARY AND RECOMMENDATIONS
●State of the literature
•The risk of adverse neurodevelopmental effects from anesthetic agents in children remains uncertain. Many clinical studies including meta-analyses have reported that compared to unexposed children, children with exposure to general anesthesia have more adverse neurodevelopmental outcomes, particularly in specific domains. Anesthetic exposure appears to have limited to no impact on the cognition domain as measured by IQ testing, but stronger association has been reported in domains of motor function and behavior. However, at this time there is inadequate evidence to directly attribute this effect to the anesthesia. (See 'Lack of definitive evidence in human studies' above.)
•Results from the only published randomized clinical trial to date suggest that a single anesthetic exposure has no effect on intelligence or on a range of other neurodevelopmental outcomes at age five years. (See 'Prospective, randomized trial' above.)
•There is one observational study reporting an association between prenatal exposure and subsequent abnormal behavioral scores, but given the limitations of the study, it does not provide adequate evidence to justify any changes in clinical practice, particularly since avoiding necessary surgery during pregnancy can have significant detrimental effects on the mother and the child. (See 'Prenatal exposure to anesthesia' above and 'The FDA warning' above.)
●What we tell parents – While children who need surgery and anesthesia have worse scores in some neurodevelopmental outcomes compared with children who do not need surgery and anesthesia, these score differences are small with unclear clinical significance, and these differences cannot yet be fully attributed to the anesthesia exposure. Children who undergo surgery and anesthesia and those who do not are different in ways that may not have been fully accounted for in the available studies. Thus, there is still uncertainty that exposure to anesthetic medications has lasting effects on children. (See 'What we tell parents and patients' above.)
●Practice implications – The potential risks of exposure to anesthesia must be weighed against the benefits of the surgical or diagnostic procedure. Given the uncertainty that any long-term effects in children are due to the anesthetic medications, and the potential for complications if necessary surgery is avoided or delayed, changes in clinical management should not be made based on the potential risk of neurotoxicity of anesthesia. (See 'The FDA warning' above.)
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