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Why Some Pediatric Neurologists Are Concerned About a New FDA Warning About Anesthesia



THE FDA ALERT advised health care professionals to “balance the benefits of appropriate anesthesia in young children and pregnant women against the potential risks” of procedures that may last longer than three hours or if multiple procedures are required in children under 3 years.

A US Food and Drug Administration advisory warning about the potential impact of anesthesia in children under 3 years old on neurocognitive outcomes has elicited concerns about its potential impact on needed surgeries and research on young children for which anesthesia is needed.

A Food and Drug Administration (FDA) “drug safety communication” warning about the effect of anesthesia on the neurodevelopment of children under the age of three has elicited concerns among some pediatric neurologists and other clinicians that the advisory could cause unnecessary delays in needed surgical and diagnostic procedures and research in young patients.

The FDA communication, issued in December 2016, noted that animal studies and some studies in children had shown that the use of general anesthesia and sedative drugs for more than three hours caused widespread loss of nerve cells in the brain and neurodevelopment delays.

The FDA also cited epidemiologic studies investigating the association between childhood anesthesia exposure and adverse neurodevelopmental outcomes published between 2009 and 2014.

For example, a 2011 study in Anesthesia & Analgesia reviewed data on 10,450 siblings born between 1999 and enrolled in the New York State Medicaid program. The exposed group included 304 children without a history of developmental or behavioral disorders who underwent surgery when they were younger than 3 years, compared with 10,146 children who did not receive any surgical procedures. The researchers found that the incidence of developmental and behavioral disorders was 128.2 diagnoses per 1,000 person-years for the exposed cohort and 56.3 diagnoses per 1,000 person-years for the unexposed cohort.

The FDA safety alert advised health care professionals to “balance the benefits of appropriate anesthesia in young children and pregnant women against the potential risks,” especially for procedures that may last longer than three hours or if multiple procedures are required in children under 3 years.

But in an editorial in the February 8 online edition of The New England Journal of Medicine (NEJM) and interviews with Neurology Today, clinicians said that some of the observational human studies cited by the FDA were compromised by methodological problems, especially confounding factors that may have accounted for adverse neurological development in children who receive anesthesia.

More recent clinical research, for example, the General Anesthesia vs. Spinal Anesthesia (GAS) study and the Pediatric Anesthesia and Neurodevelopment Assessment (PANDA) study, revealed that a brief, single exposure to general anesthesia was not associated with poorer neurodevelopmental outcomes, wrote Dean B. Andropoulous, MD, professor of anesthesiology at Baylor College of Medicine and Michael F. Greene, MD, chief of obstetrics at Massachusetts General Hospital in Boston, in the NEJM editorial.

The study, a sibling-matched observational cohort study, examined whether a single anesthesia exposure in healthy children younger than 3 years is associated with an increased risk of impaired global cognitive function (IQ) as the primary outcome, and abnormal domain-specific neurocognitive functions and behavior as secondary outcomes at ages 8 to 15 years.

Exposed children (n=105) had a single episode of general anesthesia before 3 years for elective inguinal hernia surgery and were 36 weeks' gestational age or older at birth. The unexposed cohort (n=105) were biologically related siblings closest in age (within 3 years) to the exposed child, also 36 weeks' gestational age or older at birth but with no anesthesia exposure before 3 years. The study found that mean IQ scores were not significantly different between the exposed and unexposed siblings, with both groups scoring somewhat higher than average.


Commenting on the FDA advisory, Donna Ferriero, MD, MS, professor of pediatrics and neurology and chair of the department of pediatrics at the University of California, San Francisco, said: “Unfortunately, this warning only complicates matters for parents and caregivers, as well as providers. When children and pregnant mothers must undergo anesthetic exposure even for prolonged periods for necessary surgery or procedures, options are few. Counselling now has been made much more confusing to the parents.”

“In the context of recent reassuring prospective data in humans that suggest that a single, brief exposure does not impact neurodevelopment, I suggest that this warning was not warranted or wise,” Dr. Ferriero said. “It will cause unnecessary concern and confusion for families with infants with neurological illness who need procedures requiring exposure to anesthetics and/or sedatives. Most caregivers will extrapolate the warning for prolonged exposure to minimal exposure. These warnings have already impacted our research studies. We are no longer able to provide general anesthesia for even brief brain imaging studies.”

She added, “In most cases, surgery or procedures are only recommended to patients after meticulous weighing of risks and benefits — as in the case of epilepsy surgery, rhizotomy, ventriculoperitoneal shunting, or imaging to clarify a diagnosis.”

Steven Miller, MD, head of the division of neurology at The Hospital for Sick Children in Toronto, said he was surprised by the FDA advisory, “not because this isn't an important issue, but by the certainty and severity of the warning.”

“The data from experimental studies with animals raises a clear concern about the impact of general anesthetics on the developing brain,” Dr. Miller told Neurology Today. “But what strikes me about the clinical research involving evaluation of young children exposed to anesthesia is that as the methodological rigor of the studies increase, the concerns about adverse effects decrease.”

Dr. Miller echoed concerns about the problems of confounding in earlier observational studies raised in the NEJM editorial. “For example, many children with congenital heart disease have abnormalities in brain development even before they go to surgery,” he said. “So, too, [is this true] with many babies born prematurely. So, it's hard to tease out the independent impact of anesthesia from observational studies alone.”

Dr. Miller said timing of exposure to anesthesia may be an unknown factor in the effect on neurodevelopment, a variable that will be critical to understand. “It may be that the impact of these agents is different for different parts of the brain at different stages of early life,” he said. “What that means for outcomes of infants is a critical research question.”

He noted that for some procedures, such as newborn brain MRI scans, there are alternatives to anesthesia, such as `feed-and-sleep.' “At the Hospital for Sick Children we have moved away from general anesthesia for most neonatal brain scans, using feed-and-sleep or sedation by our neonatal transport team where appropriate,” he said.

But Dr. Miller agreed with Dr. Ferriero that clinicians should not delay non-elective surgeries requiring anesthesia. “Most surgery in children under three is not elective,” he said. “I would not want to see children not undergo necessary procedures because of this potential risk of general anesthetics, which in the latest trials of brief single exposures to anesthesia are not raising a serious concern.”

Finally, Dr. Miller said he believes neurologists—because of their understanding of neurodevelopment—should be crucial partners in further research on the short and long-term effects of anesthesia and sedation.


Asked by Neurology Today for a response to the NEJM editorial, FDA spokesperson Jeremy Kahn said physicians and parents must consider many factors when deciding whether a surgical procedure should be postponed or not.

In an email, he responded with an official statement from the FDA: “The totality of published evidence to date suggests that it is unlikely for a single brief exposure to a general anesthetic to cause overt neurocognitive effects. Recent human data suggest that a single, relatively short exposure to general anesthetic and sedation drugs in infants or toddlers is unlikely to have negative effects on behavior or learning. While children do not generally undergo surgical procedures that require anesthesia and/or sedation unless the surgery is essential to their health, it may be possible to delay some procedures while delaying others is clearly not an acceptable option...The FDA will continue to monitor studies of the use of these drugs in pregnant women and children and will update the public as additional information becomes available.”

The FDA has collaborated with the International Anesthesia Research Society to form a public-private Partnership, SmartTots, under the Pediatric Anesthesia Safety Initiative ( The mission of SmartTots is to coordinate and fund research with the goal of ensuring safe surgery for infants and young children who undergo anesthesia and/or sedation. (Dr. Andropoulos, co-author of the NEJM opinion piece, is a member of the SmartTots scientific advisory board.)

Santhanam Suresh, MD, professor of anesthesiology and pediatrics at the Ann & Robert H. Lurie Children's Hospital of Chicago and co-chair of the SmartTots advisory board, said the FDA warning was based on research that was available at the time. And he noted that the FDA is partnering with IARS to study the possibility of agents that could mitigate the potential adverse effects of anesthesia, as well as further research looking at neurodevelopment of children who have been exposed to anesthesia.

In the meantime, Dr. Suresh said not enough is known to definitively make a statement about delaying surgeries or procedures. “We don't have the data to say that is necessary, so I would advise physicians to continue using their best judgement,” he said. “If you have a child in a neurological setting who is being evaluated for seizures and will likely need an MRI, I think the better part of wisdom is to get the procedure done. I would encourage physicians to consider the fact that it is far more important that the child is taken care of and that they follow through on what is needed in order for them to make a diagnosis or treat an illness.”

“I would not want to be in the position of being the one person who missed a brain tumor or a major correctable disorder in a child because we avoided the use of a general anesthetic,” Dr. Suresh said.


• Andropoulos DB, Greene MF. Perspective: Anesthesia and developing brains — Implications of the FDA warning N Engl J Med 22017; Epub 2017 Feb 8.
    • FDA Drug Safety Communication: FDA review results in new warnings about using general anesthetics and sedation drugs in young children and pregnant women:
      • DiMaggio C, Sun LS, Li G. Early childhood exposure to anesthesia and risk of developmental and behavioral disorders in a sibling birth cohort Anesth Analg 2011;113:1143–1151.