The effects of labor analgesia, particularly epidural analgesia, on neurodevelopment in children has been investigated primarily during the neonatal period.1,2 The article in this issue of Anesthesia & Analgesia by Flick et al.3 from the Mayo Clinic describes research that took a longer view and attempted to evaluate the outcome later in life. Several earlier studies have examined the association of perinatal factors and later developmental and behavioral disorders.4–6 Unlike the present study, which examined learning disability as the outcome (see accompanying editorial by Radcliffe and Bellinger7), these previous studies have focused on autism spectrum disorders. In 1991, Hattori et al.5 reported an association of autistic and developmental disorders with maternal general anesthesia during labor and delivery. A 2004 study from Western Australia identified a host of perinatal factors including maternal epidural anesthesia that were associated with the development of autism spectrum disorder.4 A 2009 study from Bilder et al.6 in Utah examined the associations of prenatal, perinatal, and neonatal factors with autism spectrum disorders. The only significant obstetric factor in this study was breech presentation.6
Fetal exposure to anesthetic and analgesic drugs has become an area of intense interest for the pediatric and obstetric anesthetic community as a result of the alarming findings from recent experimental studies suggesting that anesthetics are neurotoxic to the developing brains of immature rodents and nonhuman primates.8–14 Although the doses and durations of anesthetic exposure in these laboratory studies may not be fully analogous to those in humans undergoing operations and procedures, the findings are very concerning. Several clinical studies, including 2 from the Mayo group,15,16 have also examined the possible neurodevelopmental effects of early childhood exposure through analysis of existing data.17–19 A summary is presented in Table 1.
The conflicting results from these clinical studies can be attributed to a variety of causes: the study design, the outcome measures used, and the population under study. All of these studies involved retrospective analysis of data. The outcome end points included learning disability, diagnosis of developmental and behavior problems based on ICD-9 (International Classification of Diseases, 9th revision) coding, parental reports of behavior, teacher reports of behavior, and school achievement tests. None of these outcome end points represented specific neuropsychological functions. None of the outcome assessments used standardized measurement tools. The study populations were not representative of the ethnic, racial, cultural, and socioeconomic diversity of the United States population. The data on anesthesia exposure were not specified for drugs, duration, or age. Common to all of the studies was the selection of the age for exposure, usually before age 3 or 4 years. This seems to be appropriate given our current understanding of the time course of human brain development.
Brain development involves the processes of neurogenesis, migration, synaptogenesis, apoptosis, and myelination.20,21 These processes follow a distinct timeline in each brain region, producing differing rates of neurocognitive maturation. In rodents, the critical period of vulnerability for massive neuronal apoptosis after exposure to anesthetic drugs was at postnatal day 7.12,22,23 This particular age in rodents is the time of peak neuronal synaptogenesis. In the human brain, the timing for peak synaptogenesis proceeds from the primary sensorimotor cortex to the prefrontal cortex. Peak synaptogenesis in the primary sensorimotor cortex occurs around birth, followed by synaptogenesis in parietal and temporal association cortex at approximately 9 months. The last region to peak in synaptogenesis is that of the prefrontal cortex, at approximately age 3 years.21,24 The parietal and temporal association cortex is important in language and spatial attention. The prefrontal cortex is responsible for executive, integrative, and modulatory brain function.
An insult early in brain development could potentially not only affect the specific brain region undergoing peak synaptogenesis but could additionally delay and adversely affect the future development of other brain regions.25 Because we have no scientific data to specify the “phenotype” or the neurodevelopmental outcome after early childhood anesthetic exposure, it is difficult to isolate the period of vulnerability. One possible approach might be to incorporate our current knowledge of the periods for peak synaptogenesis in the different human brain regions as potential vulnerable periods for neurotoxicity in the developing human brain. Thus, if exposure takes place during the period of peak synaptogenesis in these discrete brain regions, the “phenotype” might be specific abnormalities in neurocognitive functions subserved by these brain regions. Therefore, the entire period from the late fetal period to 3 years of age during which peak synaptogenesis occurs in the human brain might be considered vulnerable.
Because recent laboratory studies also suggest that anesthetic drugs may interfere with other neurodevelopmental processes in addition to synaptogenesis, including neurogenesis and dendrite spine formation, consideration of the period of vulnerability may need to be further expanded to include the timing for the other neurodevelopmental processes.
The evidence from animal studies on anesthetic neurotoxicity suggests that neuroapoptosis and neurobehavioral changes occur in response to drugs with γ-aminobutyric acid A and N-methyl-D-aspartate actions.12 Interestingly, in the study by Flick et al.,3 many patients also received inhaled anesthetics as a part of the labor analgesic regimen. Of note, significantly more patients in the nonneuroaxial analgesia group received inhaled anesthetics (16%) compared with the neuroaxial analgesia group (3%). These additional exposures to known neurotoxic drugs in animals certainly complicate the interpretation of the study results. Although studies to examine whether local anesthetics are neurotoxic in humans have not yet been performed, one study in Rhesus monkeys suggests that exposure to bupivacaine used for epidural analgesia may have long-term effects.26 Golub and Germann26 found that epidural bupivacaine does not cause abnormal behavior or deficits in specific cognitive function during the neonatal period, but the animals show evidence of “developmental delay” in that their normal course of behavioral development up to 1 year was either delayed or modified.
Each year, an estimated 6 million children receive anesthesia for surgical and nonsurgical procedures,27 in addition to anesthetic exposure that accompanies many of the 4 million births in the United States.28 Whether frequently used anesthetics can adversely affect long-term neurodevelopmental outcome is a public health issue that needs to be answered. The current study adds to the literature on this topic, underscoring the value as well as the limitations of retrospective epidemiological studies. Although the results do not provide definitive answers, they may inform the design of additional studies in a more targeted and specific manner. More evidence is needed to guide clinical decision-making on the safety of anesthesia during labor and delivery as well as pediatric anesthesia. We have made much progress in the past decade in our understanding of the relative benefits and risks of labor analgesia to the mother and the newborn.29,30 We have accomplished this by integrating the results of a wide range of studies, ranging from molecular biology to clinical outcomes and epidemiology. We now need to continue the work initiated by Flick et al., and rigorously pursue the question of the long-term effects of labor analgesia or delivery anesthesia (for both cesarean and vaginal delivery) on the child.
The author gratefully acknowledges the editorial assistance by Mr. Keane Tzong.
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