Clinical Evidence for Any Effect of Anesthesia on the Developing Brain

Andrew J. Davidson, M.B.B.S., M.D., F.A.N.Z.C.A.; Lena S. Sun, M.D., F.A.A.P., D.A.B.A.


Anesthesiology. 2018;128(4):840-853. 

In This Article

Abstract and Introduction


A recent U.S. Food and Drug Administration warning advised that prolonged or repeated exposure to general anesthetics may affect neurodevelopment in children. This warning is based on a wealth of preclinical animal studies and relatively few human studies. The human studies include a variety of different populations with several different outcome measures. Interpreting the results requires consideration of the outcome used, the power of the study, the length of exposure and the efforts to reduce the confounding effects of comorbidity and surgery. Most, but not all, of the large population-based studies find evidence for associations between surgery in early childhood and slightly worse subsequent academic achievement or increased risk for later diagnosis of a behavioral disability. In several studies, the amount of added risk is very small; however, there is some evidence for a greater association with multiple exposures. These results may be consistent with the preclinical data, but the possibility of confounding means the positive associations can only be regarded as weak evidence for causation. Finally, there is strong evidence that brief exposure is not associated with any long term risk in humans.


THE US Food and Drug Administration (FDA) recently issued a change in labeling regarding the safe use of anesthetic and sedative agents (; accessed November 10, 2017).

The opening sentence states that "repeated or lengthy use of general anesthetic and sedation drugs during surgeries or procedures in children younger than 3 years or in pregnant women during their third trimester may affect the development of children's brains." This warning then suggests that brief exposure is probably safe and continues to a summary of available preclinical and human evidence. It also encourages healthcare professionals to consider the risks of delaying surgery. The issue of how, or even if, anesthetic agents affect the developing brain has been the subject of a great deal of research over the last couple of decades. There is now overwhelming preclinical evidence that most anesthetic agents can, in some situations, modulate various aspects of brain development, but there is great uncertainty over how these findings in animal models translate to clinically relevant human scenarios.[1–3] Evaluating the strengths and limitations of human evidence is essential when determining potential change in practice. Several important human studies have been published recently, and with the recent FDA warning, it is an opportune time for this review which aims to critically appraise the human evidence. This review will focus on studies that provide the strongest evidence, and will provide a summary of the current human evidence.