Letter to the Editor


Effects of anesthesia on the developing brain: can the underlying disease be ignored? 

SIR—Very few issues (if any) within pediatric anesthesia have created so much concern and emotional gravity than the possibility that general anesthetics might be neurotoxic in the developing brain. Fortunately, contrary to the plethora of positive animal studies, it has proven rather difficult to demonstrate a human corollary to this phenomenon. Consequently, if it exists in humans, anesthesia-related neurotoxicity must be vague or present only in a subset of (genetically?) susceptible infants, otherwise it would have been easy to demonstrate and it would most likely have been suspected many years ago. In two nationwide, unselected follow-up studies of the Danish birth cohorts 1986–1990 from our group comprising (the largest samples published so far) neonates and infants undergoing inguinal hernia repair in infancy and pyloric stenosis repair before the age of 3 months, academic achievements in 9th grade (aged 15–16 years) were similar to a 5% randomly selected control sample when adjusted for confounding factors (e.g., age, gender, congenital malformations, maternal age, and parental level of education) (1,2).

However, exposed children had a slightly higher nonattainment rate (compatible with the existence of a susceptible subgroup?). Interestingly, the above-mentioned confounders more strongly affected academic achievements than anesthesia and surgical exposure. This was the background for my recent review article on this topic (3). The review article was a commissioned paper for the themed January 2015 issue of Pediatric Anesthesia containing various review articles on challenging orthodoxy in pediatric anesthesia many of which had predetermined and bombastic titles such as mine. Of course, my review article was meant as a “provocative” input into the current debate on this topic. However, if one reads the manuscript in full, the reader would acknowledge that the situation is a bit more complicated. I completely concur with Drs. Warner and Flick’s conclusion of their letter (4) addressing my review article that: Although anesthesia-related neurotoxicity may be a minor problem, the jury is still out there.

In their letter, Drs. Warner and Flick also question the conclusion drawn in our recent cohort study comprising all children undergoing neurosurgical procedures in Denmark during 1986–1990, that “….pooling of data from multiple surgeries (and diagnosis) in studies on anesthesia-related neurotoxicity and the developing brain is not a legitimate approach…..” (5). In Denmark, later academic outcomes (9th grade) in infants undergo- ing inguinal and pyloric stenosis repair are comparable to the background population (1,2) and much better than in infants undergoing neurosurgeries (5). Additionally, contrary to children undergoing, e.g., inguinal hernia and pyloric stenosis repair, it is very common for children undergoing neurosurgeries to have additional anesthetic and surgical exposures in our Danish registers. Thus, when pooling data from different surgeries and diagnosis in anesthesia-related neurotoxicity cohort studies, this will impact the results obtained. Moreover, in an ongoing study from our group comprising children undergoing oral cleft surgery (a somewhat minor sur- gery and presumably a more homogeneous group), we found important differences in outcomes (mortality and academic achievements in 9th grade) depending on whether the child had undergone cleft lip, cleft palate, or both cleft lip and palate repair. Therefore, I will maintain that stratification according to diagnosis/surgery is indeed necessary when conducting human cohort studies on the association between anesthesia/surgery exposure in early life and later cognitive outcome.

Tom G. Hansen
Department of Anaesthesia and Intensive Care – Pediatric Section
Odense University Hospital, Odense C, Denmark
Clinical Institute – Anesthesiology
University of Southern Denmark, Odense C, Denmark
Email: [email protected]

© 2015 John Wiley & Sons Ltd Pediatric Anesthesia 25 (2015) 431–439  Conflicts of interest No conflicts of interest declared.  doi:10.1111/pan.12632



1 Hansen TG, Pedersen JK, Henneberg SW et al. Academic performance in adolescence after inguinal hernia repair in infancy: a nationwide cohort study. Anesthesiology 2011; 114: 1076– 1085.

2 Hansen TG, Pedersen JK, Henneberg SW et al. Educational outcome following pyloric stenosis repair before 3 months of age: a nationwide cohort study. Pediatr Anesth 2013; 23: 883–890.

3 Hansen TG. Anesthesia-related neurotoxic- ity and the developing anim al brain is not a significant problem in children. Pediatr Anesth 2015; 25:65–72.

4 Warner DO, Flick RP. Effects of anesthesia and surgery on the developing brain: prob- lem solved? Pediatr Anesth 2015; 25: 435– 436.

5 Hansen TG, Pedersen JK, Henneberg SW et al. Neurosurgical conditions and proce- dures in infancy are associated with mortality and academic performances in adolescence: a nationwide cohort study. Pediatr Anesth 2015; 25: 186–192.