Update on developmental anesthesia neurotoxicity

Transcription

1 REVIEW C URRENT OPINION Update on developmental anesthesia neurotoxicity Laszlo Vutskits a,b and Andrew Davidson c,d Purpose of review Adverse long-term impact of general anesthesia on the developing brain is a widely discussed and controversial issue with potential public health relevance. The goal of this article is to give insights into the most recent experimental and clinical observations aimed to advance our understanding in this field. Recent findings Recent investigations demonstrate long-term behavioral consequences of early-life anesthesia exposure in nonhuman primates under experimental conditions that are translationally relevant to human clinical practice. Converging evidence from rodent experiments strongly suggest that anesthetics exert developmental stage-dependent and context-dependent impact on developing neuronal circuitry and, therefore, may induce lasting changes in neuronal plasticity. Although three recent population-based human studies found a strong evidence for small increase in risk, the two most robust studies (General Anaesthesia compared to Spinal anaesthesia trial and Pediatric Anesthesia Neurodevelopment Assessment) did not find an association between brief anesthesia exposure and poor neurodevelopmental outcome. Summary Experimental data with reasonable translational relevance suggest that early-life exposure to general anesthetics can induce lasting behavioral and cognitive deficits. In contrast, human studies provide, at best, mixed evidence about developmental anesthesia neurotoxicity. Future research, both experimental and human, is needed to clarify this important issue. Keywords anesthesia, cognition, development, neuroplasticity, neurotoxicity INTRODUCTION Altered behavior in young children following anesthesia and surgery was suggested to be a potential issue more than 60 years ago [1]. Ever since these original observations, and particularly during the past 15 years, a tremendous amount of both experimental and clinical research has been devoted to study the potential for general anesthetics to cause harm to the developing central nervous system [2]. It is clear that there is a biological rationale for neurotoxic potential of general anesthetics on the immature brain, and laboratory data convincingly demonstrate age-dependent, dose-dependent and exposure length-dependent effects of these drugs on a variety of morphofunctional parameters as well as on behavior [2]. However, the translational relevance of these observations remains highly debated. Although some human studies demonstrate an association between exposure to anesthesia/surgery during early postnatal life and subsequent neurocognitive or behavioral deficits, others suggest the absence of such a link. Therefore, and despite all the past and currently ongoing effort, we are still unable to clearly discern if, and to what extent, general anesthetics impair brain development in human infants. Several important questions remain open in the laboratory as well as in the clinical setting, and intense research is under way to further tackle these issues (reviewed in Vutskits and Xie [2]). Some of the most important studies have appeared recently. The aim of the current review is to focus on some of the landmark observations obtained over the period of the past 2 years. We will first discuss new experimental observations that may help us to better understand the functional a Department of Anesthesiology, Pharmacology and Intensive Care, University Hospital of Geneva, b Department of Basic Neurosciences, University of Geneva Medical School, Geneva, Switzerland, c Department of Anaesthesia, Royal Children s Hospital and d Melbourne Children s Trials Centre, Murdoch Childrens Research Institute, Melbourne, Victoria, Australia Correspondence to Laszlo Vutskits, Department of Anesthesiology, Pharmacology and Intensive Care, University Hospital of Geneva, 4, rue Gabrielle-Perret-Gentil, 1205 Geneva, Switzerland. Tel: ; laszlo.vutskits@unige.ch Curr Opin Anesthesiol 2017, 30: DOI: /ACO Copyright ß 2017 Wolters Kluwer Health, Inc. All rights reserved.

2 Pediatric anesthesia KEY POINTS General anesthetics are powerful modulators of neuronal activity, and there is a clear biological rationale for that these drugs interfere with physiological brain development. Experimental observations, from earthworms to nonhuman primates, convincingly demonstrate that general anesthetics can induce lasting developmental stage-dependent and context-dependent morphological, functional and behavioral changes. Population-based recent human epidemiological observations found a strong evidence for small increase in risk, but the two most robust studies (General Anaesthesia compared to Spinal anaesthesia trial and Pediatric Anesthesia Neurodevelopment Assessment) did not find an association between brief anesthesia exposure and poor neurodevelopmental outcome. relevance of developmental anesthesia neurotoxicity. This will then be followed by a critical overview of recently published major clinical studies in this domain. EXPERIMENTAL DATA One of the most important advances in the field of experimental anesthesia neurotoxicity research over the past 2 years is related to the publication of behavioral follow-up studies conducted in nonhuman primates (NHPs) following early-life anesthesia exposure. These studies were designed to apply translationally relevant anesthesia protocols in terms of neurodevelopmental stage as well as exposure length and included continuous reliable monitoring of physiological parameters during anesthesia. In a first series of investigations, to mimic repeated exposure to anesthesia in early childhood, Raper et al. [3 ] exposed 6 10-day-old infant rhesus (Rh) monkeys to a 4-h long sevoflurane anesthesia, and this drug administration protocol was repeated 14 and 28 days later. When socioemotional behavior was evaluated at the age of 6 months using the human intruder task that allows assessment of emotional reactivity based on the salience of the social threat presented by the intruder, infant Rh monkeys who received multiple exposures to sevoflurane during the first month of life exhibited increased anxiety compared with control patients undergoing brief maternal separation. Importantly, the different durations of maternal separation between the sevoflurane and control groups did not impact on mother infant bond, further suggesting that the behavioral difference between exposed and nonexposed animals is related to the anesthesia exposure per se [4]. In a second set of experiments, the motor and behavioral consequences of a single as well as repeated 5-h long exposures to isoflurane in infant Rh macaques were assessed up to 1 year after drug administration. In this work, animals who received multiple isoflurane exposures exhibited long-term impairments affecting both motor and socioemotional aspects of behavior, whereas no such effects were found either in the control group or following single exposure to isoflurane [5]. The converging conclusion of these two independent studies is that multiple exposures to general anesthesia in early life result in long-term behavioral consequences. The major strength of these observations obtained in NHPs lies in their human translational value when compared with experimental data obtained in rodents. Indeed, although exposure length-dependent long-term neurobehavioral and cognitive impact of early-life anesthesia administration have been repeatedly demonstrated in mice and rats, the significance of these results in terms of human relevance has been strongly questioned because of a multitude of factors precluding the translatability of these observations to humans. Experimentation in NHPs is particularly well suited to circumvent many of these issues as the neurodevelopmental stage at birth in these species is much closer to humans. Also, due to the much larger size of the NHP at birth, complex physiological monitoring and, thereby, the maintenance of systemic homeostasis in a physiological range during anesthesia is feasible. This, in turn, allows us to eliminate some important confounding homeostatic variables associated with the potentially depressant effects of anesthesia on respiration and cardiovascular function, and allows us to mechanistically dissect the specific contribution of anesthetics to neuromorbidity in the immature brain. This is a substantial advantage compared with the human situation in which separating the impact of anesthesia and surgery on the developing brain is, at best, very difficult. Last, but not least, as the two research groups are planning to pursue behavioral follow-up over the period of the next few years, these NHP trials will provide us with useful information on long-term functional outcome in these early-life anesthesia-exposed monkey populations. Mechanistic understanding of the effects of general anesthetics on the developing brain at the molecular, cellular and network levels is not only of academic interest but will also help in the development of any future protective strategies and inform the design of future clinical trials. In this regard, an interesting line of research has tackled the influence of anesthetics on immature neuronal circuitry. Using electron microscopic analysis of hippocampal Volume 30 Number 3 June 2017

3 Update on developmental anesthesia neurotoxicity Vutskits and Davidson tissue ultrastructure in adult rats having received sevoflurane anesthesia in the early postnatal period, Amrock et al. [6 ] have investigated the long-term effects of a single exposure or multiple exposures with equivalent total duration of exposure on synaptic density as well as on the number of mitochondria in synaptic terminals. They found that although even a single exposure to this anesthetic decreased synaptic density, repeated exposure led to a greater synapse loss. Interestingly, the sevofluraneinduced reduction in the number of mitochondria in synaptic terminals was correlated with the total anesthetic exposure time but not with the number of exposures. A detailed ultrastructural analysis of the rat subiculum 5 days following anesthesia administration at postnatal day 7 revealed a significant decrease in the number and strategic localization of presynaptic vesicles within the nerve terminals [7]. In line with these structural observations, electrophysiological recordings also indicate lasting modifications in ion channel properties that control neuronal excitability [8,9]. Impaired inhibitory neurotransmission may also reflect early-life anesthesia exposure-induced modifications of interneuronal phenotypes in the nervous system [10]. Finally, new experimental evidence suggests that the effects of anesthetics on neuronal network development depend upon the efficacy of GABA A receptor-mediated inhibition controlled by the developmental stage-dependent upregulation of the potassium-chloride cotransporter 2 [11]. The ensemble of these experimental data brings strong arguments in favor of considering general anesthetics as powerful developmental stage-dependent modulators of neuronal plasticity during critical periods of postnatal development. This concept is an appealing framework to explain behavioral and cognitive deficits following anesthesia exposure and provides a plausible alternative to the concept of neurotoxicity referring principally to just cell death or brain injury. To foster the translational relevance of animal data as well as to carefully design future human trials, many important questions remain to be answered in the laboratory. One fundamental unknown issue is whether the mechanisms implicated in the maintenance of the anesthetic states are the same as those inducing sustained effects on neuronal structure and function. We also do not know how anesthetic-induced structural changes translate into cognitive deficits. Moreover, we do not understand why the increased vulnerability of neuronal architecture is restricted to well defined, region-specific time windows during development instead of persisting through the whole lifespan. Future work is needed to dissect how the pathophysiological context and the related changes in systemic homeostasis modify the impact of anesthetics on neuronal networks. Related to this point, NHP experimentation should explore how concomitant surgery modifies anesthetic-related neuromorbidity. Most importantly, if anesthesia exposure during early life is causally linked to subsequent neuromorbidity, developing therapeutic strategies to prevent or reduce these effects is of utmost importance. Increasing our understanding on these issues will have a major impact on future clinical research agenda. HUMAN STUDIES Up until recently, the vast majority of human studies were retrospective cohort studies. Some were large, population-based studies using group-administered outcomes such as school performance or a new diagnosis of a neurodevelopmental disorder or a learning disability. Others have used more detailed psychometric tests in smaller and often preexisting cohorts. The findings were mixed but generally found weak evidence for an association between exposure in early childhood and increased risk of later adverse neurodevelopmental outcome [12,13]. The association was stronger in those exposed to multiple anesthetics. In those studies that used more detailed psychometric testing, deficits were found in language, cognition, memory and listening comprehension tests [14 18]. The variation in results from these studies may be explained by differing ages at exposure and differing outcome measures. The major weakness of all cohort studies is confounding; children who have anesthesia often have other problems, which in themselves put the child at risk of poor neurodevelopmental outcome. It is plausible that the stress of surgery itself or several other aspects of perioperative care may also have an impact. Various adjustments can attempt to reduce the impact of such confounding but only to a limited degree. Causation simply cannot be established with cohort studies. Confounding may also explain why the evidence is greater with multiple exposures compared with single exposures; children with greater comorbidity are more likely to need multiple procedures. In summary, it was very difficult to draw any robust conclusions from the human data [12]. Recently, however, several human studies have added important new evidence that, when considered with the animal data, do allow us to draw some cautious conclusions. The Pediatric Anesthesia Neurodevelopment Assessment (PANDA) study is probably the most robust of the cohort studies yet to be published [19 ]. This was an ambidirectional Copyright ß 2017 Wolters Kluwer Health, Inc. All rights reserved

4 Pediatric anesthesia cohort study performed at four tertiary US pediatric hospitals. A total of 105 children aged 8 15 years were identified who had hernia repair before 3 years of age and matched with siblings who were of similar age but not had hernia repair. A detailed battery of psychometric tests was given with the fullscale IQ being the primary outcome. The exposed group was healthy at the time of surgery and had a median exposure of 80 min of anesthesia. The fullscale IQ was 111 in the exposed group and 111 in the unexposed group, with a difference between groups (exposed unexposed) of only 0.2 points [95% confidence interval (CI) 2.6 to 2.9]. The difference in subdomains was 0.5 (95% CI 2.7 to 3.7) in performance IQ and 0.5 (95% CI 3.2 to 2.2) in the verbal IQ. The 95% CIs are all well within a boundary that might be regarded as clinically insignificant, and hence the study can be regarded as showing strong evidence for no difference. There was also no difference between groups seen in the other tests assessing the domains of memory and learning, motor and processing speed, language, attention, executive function and visuospatial skills. There was limited evidence for a difference in some aspects of behavior, which may be due to the sex difference. The authors performed subanalyses looking at those with longer exposure and found no evidence for a difference in the primary outcome in those exposed to up to 120 min of anesthesia. They also found that age of exposure had no impact on the outcome. Three large population-based studies have also been recently published [20,21,22 ]. Two very similar Canadian studies examined the association between surgery in young children and later performance in the Early Development Index (EDI). The EDI is a test of readiness for school and is administered at around 5 years of age. It has five domains (physical health and wellbeing, social knowledge and competence, emotional health and maturity, language and cognitive development, communication skills and general knowledge). The study from Ontario matched children who had surgery before the EDI, with controls [20 ]. They excluded children with physical disability, health-related causes of impaired development and any diagnosis of a behavioral or learning problem. Children were matched on gestational age, mother s age, rurality, sex and year and quartile of birth. The primary outcome was vulnerability, defined as having any EDI domain in the lowest 10%. The analysis was adjusted for aboriginal status, age and household income. They found weak evidence for a small difference in incidence of vulnerability; 25.0% in the exposed group compared with 25.6% in the unexposed group. The difference was most pronounced in the physical health and wellbeing, and social knowledge and competence domains. In subanalyses, there was only evidence for a difference in the children aged 2 4 years at time of exposure. There was insufficient power to conclude whether or not there was no difference in the 0 2-year age group. They also found no evidence that number of exposures had an impact; however, the study was sufficiently not powered to make definitive comment on the impact of multiple exposures. The study from Manitoba was subtly different [21 ]. They compared 4470 children who had surgery before the age of 4 years with matched controls, excluding children with any diagnosis of developmental disability. They matched children according to gestational age, maternal age, rurality, income quartile, sex and year of birth and in their analysis adjusted for welfare status, being small for dates at birth, mother s age, child s age and John Hopkins Resource Utilization Band. Like the Ontario study, they found strong evidence for a very small difference with exposed children doing slightly worse. Unlike the Ontario study, the effect was greatest in communication skills and general knowledge, and language and cognitive development domains. They found no evidence for a difference between single and multiple exposure and found strong evidence for an interaction between age of exposure and outcome with the risk being greater in older children. A Swedish study compared children who had received one anesthetic prior to 4 years of age with matched controls [22 ]. They also compared 3640 children with multiple anesthetics. The primary outcome was school grade at 16 years of age, and a secondary outcome was IQ in a subset of boys who were tested as part of their national military service. The analysis was adjusted for sex, month of birth, gestational age, Apgar score, parental education, household income, cohabiting parents and number of siblings. Like the Canadian studies, they found strong evidence for a very small difference. One exposure before age 4 years was associated with a mean difference of 0.41% (95% CI %) lower school grades and 0.97% (95% CI %) lower IQ test scores. In subanalysis, the impact was greatest with ear, nose and throat surgery, and the impact was greater in the children exposed at an older age. There was weak evidence that the impact was greater in multiple exposures. The General Anaesthesia compared to Spinal anaesthesia (GAS) trial is the only randomized trial that has examined neurodevelopment after different anesthetic exposures in children [23 ]. In the Volume 30 Number 3 June 2017

5 Update on developmental anesthesia neurotoxicity Vutskits and Davidson multicenter trial, 722 infants were randomized to awake-regional or sevoflurane general anesthesia for inguinal hernia repair. The median duration of anesthesia in the general anesthesia group was 54 min. The primary outcome is IQ assessed at 5 years of age. These results will not be available until Neurodevelopment assessed by the Bayley-III at 2 years of age was a secondary outcome. For this analysis, the cognitive domain was the primary outcome of interest. The analysis was adjusted for gestational age. The difference in the cognitive composite score was 0.17 (95% CI 2.30 to 2.64). This was within the predefined equivalence margin of 5 points providing strong evidence for no different between groups. There was also strong evidence of equivalence in all the other four domains of the Bayley-III: Language, Motor, Social Emotional and Adaptive Behavior. There was no difference in results comparing intention-to-treat and as-per-protocol analyses, implying that failed awake regional cases did not bias the outcome, and no difference between multiple imputation and complete case analyses, implying that loss to follow-up did not bias the results. It must be noted however that neurodevelopmental testing at 2 years of age is inherently limited (especially in testing higher executive function and some aspects of memory), and hence the importance of awaiting the results when the children are tested at 5 years of age [24]. The above studies were driven by pediatric anesthetists. Neonatologists have also been studying the impact of surgery on neurodevelopment. Over the last decades, there have been several studies demonstrating an association between a number of neonatal surgeries and increased risk of poor neurodevelopmental outcome. Recently, Newton et al. [25] reviewed children that had tracheoesophageal fistula repair and found that 53% experienced neurodevelopmental delay requiring referral to early intervention services. A recent meta-analysis of 23 studies found developmental delay in 23% of children who had neonatal surgery for noncardiac anomalies with mean neurodevelopmental outcome scores 0.5 SDs below the normal population [26 ]. INTERPRETING THE HUMAN DATA The recent studies allow us to draw some cautious conclusions. The two most robust studies (GAS and PANDA) found no evidence for an association between brief exposure less than 1 2 h and poor neurodevelopmental outcome. The three population-based studies found strong evidence for small increase in risk. This can still be explained by confounding. The three population-based studies also found stronger evidence for an association in children older than 2 years compared with infants. This is in contrast to preclinical data that would suggest that the opposite should be found. This provides some evidence that the association seen in these studies is not related to the changes seen in preclinical studies. The impact of multiple exposures remains unclear. The recent studies had limited power to answer this question and once again, they cannot rule out confounding explaining any greater association seen with multiple exposures. Most importantly, PANDA, GAS and the three population-based studies looked exclusively or predominantly at children with exposures of less than 2 h. There are still very little human data about longer exposures. Stolwijk et al. s meta-analysis does not specifically mention length of surgery but it is likely that these cases were indeed longer than 2 h. Thus, although many things may explain this association, the available human data cannot rule out a causative association between long exposure and poor neurodevelopmental outcome. CONCLUSION There is ample experimental evidence suggesting that administration of general anesthetics during early postnatal life can induce a variety of lasting morphological and functional changes in the developing central nervous system. The underlying mechanisms have been partially revealed and suggest a complex developmental stage-dependent and context-dependent modulatory role for these drugs in neuronal network function. Recent NHP experiments with more direct translational relevance revealed persistent behavioral abnormalities upon exposure to anesthetics. Populationbased human epidemiological studies provide mixed evidence concerning the relevance of developmental anesthesia neurotoxicity to the clinical situation. However, a recent prospective trial and a well designed ambidirectional cohort study using robust psychometric outcome measures did not show an association between short anesthesia exposures and neuromorbidity. Very little is known about the impact of longer exposure times on subsequent behavior and cognitive function. Acknowledgements None. Financial support and sponsorship None. Conflicts of interest There are no conflicts of interest Copyright ß 2017 Wolters Kluwer Health, Inc. All rights reserved

6 Pediatric anesthesia REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest 1. Eckenhoff JE. Relationship of anesthesia to postoperative personality changes in children. AMA Am J Dis Child 1953; 86: Vutskits L, Xie Z. Lasting impact of general anaesthesia on the brain: mechanisms and relevance. Nat Rev Neurosci 2016; 17: Raper J, Alvarado MC, Murphy KL, Baxter MG. Multiple anesthetic exposure in infant monkeys alters emotional reactivity to an acute stressor. Anesthesiology 2015; 123: This is the first study showing that translationally relevant anesthesia protocols can induce behavioral changes in nonhuman primates. 4. Raper J, Bush A, Murphy KL, et al. Multiple sevoflurane exposures in infant monkeys do not impact the mother infant bond. Neurotoxicol Teratol 2016; 54: Coleman K, Robertson ND, Dissen GA, et al. Isoflurane anesthesia has longterm consequences on motor and behavioral development in infant rhesus macaques. Anesthesiology 2017; 126: Amrock LG, Starner ML, Murphy KL, Baxter MG. Long-term effects of single or multiple neonatal sevoflurane exposures on rat hippocampal ultrastructure. Anesthesiology 2015; 122: This rodent study, using electron microscopic analysis, elegantly demonstrates that even brief exposures to anesthetics can induce long-lasting changes in synapse architecture. 7. Lunardi N, Oklopcic A, Prillaman M, et al. Early exposure to general anesthesia disrupts spatial organization of presynaptic vesicles in nerve terminals of the developing rat subiculum. Mol Neurobiol 2015; 52: DiGruccio MR, Joksimovic S, Joksovic PM, et al. Hyperexcitability of rat thalamocortical networks after exposure to general anesthesia during brain development. J Neurosci 2015; 35: Joksovic PM, Lunardi N, Jevtovic-Todorovic V, Todorovic SM. Early exposure to general anesthesia with isoflurane downregulates inhibitory synaptic neurotransmission in the rat thalamus. Mol Neurobiol 2015; 52: Osterop SF, Virtanen MA, Loepke JR, et al. Developmental stage-dependent impact of midazolam on calbindin, calretinin and parvalbumin expression in the immature rat medial prefrontal cortex during the brain growth spurt. Int J Dev Neurosci 2015; 45: Puskarjov A, Fiumelli H, Briner A, et al. K-Cl cotransporter 2-mediated Cl-extrusion determines developmental stage-dependent impact of propofol anesthesia on dendritic spines. Anesthesiology 2017; 126: Lei SY, Hache M, Loepke AW. Clinical research into anesthetic neurotoxicity: does anesthesia cause neurological abnormalities in humans? J Neurosurg Anesthesiol 2014; 26: Wang X, Xu Z, Miao CH. Current clinical evidence on the effect of general anesthesia on neurodevelopment in children: an updated systematic review with meta-regression. PLoS One 2014; 9:e Ing CH, DiMaggio CJ, Malacova E, et al. Comparative analysis of outcome measures used in examining neurodevelopmental effects of early childhood anesthesia exposure. Anesthesiology 2014; 120: Ing C, DiMaggio C, Whitehouse A, et al. Long-term differences in language and cognitive function after childhood exposure to anesthesia. Pediatrics 2012; 130:e476 e Backeljauw B, Holland SK, Altaye M, Loepke AW. Cognition and brain structure following early childhood surgery with anesthesia. Pediatrics 2015; 136:e1 e Stratmann G, Lee J, Sall JW, et al. Effect of general anesthesia in infancy on long-term recognition memory in humans and rats. Neuropsychopharmacology 2014; 39: Ing C, Wall MM, DiMaggio CJ, et al. Latent class analysis of neurodevelopmental deficit after exposure to anesthesia in early childhood. J Neurosurg Anesthesiol [Epub ahead of print] 19. Sun LS, Li G, Miller TL, et al. Association between a single general anesthesia exposure before age 36 months and neurocognitive outcomes in later childhood. JAMA 2016; 315: This is by far the most robust cohort study yet to be published. It demonstrates strong evidence for no association between anesthesia exposure and detailed psychometric testing. 20. O Leary JD, Janus M, Duku E, et al. A population-based study evaluating the association between surgery in early life and child development at primary school entry. Anesthesiology 2016; 125: This large population-based study found strong evidence for a weak association between anesthesia in early childhood and some tests of school readiness. 21. Graham MR, Brownell M, Chateau DG, et al. Neurodevelopmental assessment in kindergarten in children exposed to general anesthesia before the age of 4 years: a retrospective matched cohort study. Anesthesiology 2016; 125: This large population-based study also found strong evidence for a weak association between anesthesia in early childhood and some tests of school readiness. They also found a strong age effect the association being stronger in those exposed at age 2 4 years compared with 0 2 years. 22. Glatz P, Sandin RH, Pedersen NL, et al. Association of anesthesia and surgery during childhood with long-term academic performance. JAMA Pediatr 2017; 171:e This large nationwide population-based study also found strong evidence for a weak association between anesthesia in early childhood and some tests of school readiness. Once again, the association was stronger in those exposed in the 2 4-year age band. 23. Davidson AJ, Disma N, de Graaff JC, et al. Neurodevelopmental outcome at 2 years of age after general anaesthesia and awake-regional anaesthesia in infancy (GAS): an international multicentre, randomised controlled trial. Lancet 2016; 387: This is the only trial to specifically examine the impact of anesthesia on neurodevelopmental outcome. Results at 2 years of age indicate no difference between awake regional and brief general anesthesia. The results are limited as tests at 2 years of age are inherently limited. 24. Warner DO, Flick RP. Anaesthetics, infants, and neurodevelopment: case closed. Lancet 2016; 387: Newton LE, Abdessalam SF, Raynor SC, et al. Neurodevelopmental outcomes of tracheoesophageal fistulas. J Pediatr Surg 2016; 51: Stolwijk LJ, Lemmers PM, Harmsen M, et al. Neurodevelopmental outcomes after neonatal surgery for major noncardiac anomalies. Pediatrics 2016; 137:e This meta-analysis examines the impact of surgery in the neonatal period, demonstrating strong evidence for an association with poor neurodevelopmental outcome Volume 30 Number 3 June 2017