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Propofol retards fetal neurodevelopment: Does propofol have neurotoxic effects?
Neurotoxicology and Teratology 46 (2014) 77
Contents lists available at ScienceDirect
Neurotoxicology and Teratology journal homepage: www.elsevier.com/locate/neutera
Propofol retards fetal neurodevelopment: Does propofol have neurotoxic effects? To the Editor: The recent article by Li et al. (2014), focusing on the fetal impact of maternal sedation, showed that propofol exposure during pregnancy can prolong maturation of physical features and retard the development of motor coordination and reflexes in offspring. However, we caution against the overinterpretation of associations in the absence of fetal monitoring. To monitor the status of the experimental preparation the authors monitored maternal blood values and vital signs but did not assess fetal environment or monitor fetal heart rate. First, the authors induced sedation but not anesthesia by using subanesthetic doses of propofol to exclude the possibility that neurotoxicity is a direct effect of significant metabolic and respiratory derangements induced by anesthetic exposure. But as we know, anesthetic sensitivity varies obviously with age. In some cases, even subanesthetic concentrations (0.7 minimal alveolar concentration) of inhalational anesthetics could induce progressive acidosis and hypoglycemia in neonatal mice (Loepke et al., 2008). Although the maternal blood gas tensions have been reported to be normal, the fetal internal environment might be experiencing drastic fluctuation, which could only be detected by analyzing arterial or venous blood samples from the umbilical cord, but not blood samples from maternal tail veins. It is, therefore, possible that the long-term neurobehavioral abnormalities after a 2-hour propofol infusion could be related to propofol-induced acidosis or hypoglycemia rather than a neurotoxic effect of the drug on neurodevelopment, as the authors proposed. Second, during sedation, maternal hemodynamic stability alone cannot guarantee adequate fetal conditions. Fetal heart rate can be significantly reduced by general anesthetics, even when maternal hemodynamics remains stable (Palanisamy, 2012). Persistent fetal bradycardia can indicate fetal distress, which can result in irreversible brain injury and long-term neurodevelopmental deficits. Thus, we assert that the question of whether retarded neurodevelopment is a direct effect of propofol on the brain or an effect of fetal distress or metabolic changes remains unanswered. In addition, the authors chose to administer propofol to pregnant rats on gestation day 18 in an attempt to model exposures corresponding to late in the first trimester of pregnancy in humans. However, to the best of our knowledge, there are no human data that indicate neurotoxicity or teratogenicity due to clinical sedation during this period. Prenatal propofol exposure only affects neurogenesis and neuronal migration and induces cell death during the second and third trimesters. However, considering the strong compensatory capacity of the immature brain, the net effect may be the preservation of neuronal density and neurocognitive function in adulthood. This may explain why prenatal exposure to isoflurane actually decreases neuroapoptosis and improves subsequent spatial memory retention in rats (Li et al., 2007).
http://dx.doi.org/10.1016/j.ntt.2014.10.002 0892-0362/© 2014 Published by Elsevier Inc.
The authors are to be commended for attempting the difficult task of exploring the neurotoxic effects of prenatal sedation. However, more rigorous animal monitoring, including fetal parameters are needed before a direct link can be made between sedative use during pregnancy and postnatal long-term neurodevelopmental deficits. Conflict of interest statement The authors have no conflict of interest to declare. References Li Y, Liang G, Wang S, Meng Q , Wang Q , Wei H. Effects of fetal exposure to isoflurane on postnatal memory and learning in rats. Neuropharmacology 2007;53:942–50. Li J, Xiong M, Alhashem HM, Zhang Y, Tilak V, Patel A, et al. Effects of prenatal propofol exposure on postnatal development in rats. Neurotoxicol Teratol 2014;43:51–8. Loepke AW, Istaphanous GK, McAuliffe 3rd JJ, Miles L, Hughes EA, McCann JC, et al. The effects of neonatal isoflurane exposure in mice on brain cell viability, adult behavior, learning, and memory. Anesth Analg 2008;108:90–104. Palanisamy A. Maternal anesthesia and fetal neurodevelopment. Int J Obstet Anesth 2012; 21:152–62.
Deshui Yu Guangyun Sun⁎ Department of Anesthesiology, The Second People's Hospital of Yibin, Yibin, Sichuan, PR China ⁎Corresponding author at: Department of Anesthesiology, The Second People's Hospital of Yibin, No. 96 North Street, Yibin 644000, Sichuan, PR China. Tel./fax: +86 831 8255069. E-mail address: [email protected] (G. Sun).
3 June 2014
Contents lists available at ScienceDirect
Neurotoxicology and Teratology journal homepage: www.elsevier.com/locate/neutera
Propofol retards fetal neurodevelopment: Does propofol have neurotoxic effects? To the Editor: The recent article by Li et al. (2014), focusing on the fetal impact of maternal sedation, showed that propofol exposure during pregnancy can prolong maturation of physical features and retard the development of motor coordination and reflexes in offspring. However, we caution against the overinterpretation of associations in the absence of fetal monitoring. To monitor the status of the experimental preparation the authors monitored maternal blood values and vital signs but did not assess fetal environment or monitor fetal heart rate. First, the authors induced sedation but not anesthesia by using subanesthetic doses of propofol to exclude the possibility that neurotoxicity is a direct effect of significant metabolic and respiratory derangements induced by anesthetic exposure. But as we know, anesthetic sensitivity varies obviously with age. In some cases, even subanesthetic concentrations (0.7 minimal alveolar concentration) of inhalational anesthetics could induce progressive acidosis and hypoglycemia in neonatal mice (Loepke et al., 2008). Although the maternal blood gas tensions have been reported to be normal, the fetal internal environment might be experiencing drastic fluctuation, which could only be detected by analyzing arterial or venous blood samples from the umbilical cord, but not blood samples from maternal tail veins. It is, therefore, possible that the long-term neurobehavioral abnormalities after a 2-hour propofol infusion could be related to propofol-induced acidosis or hypoglycemia rather than a neurotoxic effect of the drug on neurodevelopment, as the authors proposed. Second, during sedation, maternal hemodynamic stability alone cannot guarantee adequate fetal conditions. Fetal heart rate can be significantly reduced by general anesthetics, even when maternal hemodynamics remains stable (Palanisamy, 2012). Persistent fetal bradycardia can indicate fetal distress, which can result in irreversible brain injury and long-term neurodevelopmental deficits. Thus, we assert that the question of whether retarded neurodevelopment is a direct effect of propofol on the brain or an effect of fetal distress or metabolic changes remains unanswered. In addition, the authors chose to administer propofol to pregnant rats on gestation day 18 in an attempt to model exposures corresponding to late in the first trimester of pregnancy in humans. However, to the best of our knowledge, there are no human data that indicate neurotoxicity or teratogenicity due to clinical sedation during this period. Prenatal propofol exposure only affects neurogenesis and neuronal migration and induces cell death during the second and third trimesters. However, considering the strong compensatory capacity of the immature brain, the net effect may be the preservation of neuronal density and neurocognitive function in adulthood. This may explain why prenatal exposure to isoflurane actually decreases neuroapoptosis and improves subsequent spatial memory retention in rats (Li et al., 2007).
http://dx.doi.org/10.1016/j.ntt.2014.10.002 0892-0362/© 2014 Published by Elsevier Inc.
The authors are to be commended for attempting the difficult task of exploring the neurotoxic effects of prenatal sedation. However, more rigorous animal monitoring, including fetal parameters are needed before a direct link can be made between sedative use during pregnancy and postnatal long-term neurodevelopmental deficits. Conflict of interest statement The authors have no conflict of interest to declare. References Li Y, Liang G, Wang S, Meng Q , Wang Q , Wei H. Effects of fetal exposure to isoflurane on postnatal memory and learning in rats. Neuropharmacology 2007;53:942–50. Li J, Xiong M, Alhashem HM, Zhang Y, Tilak V, Patel A, et al. Effects of prenatal propofol exposure on postnatal development in rats. Neurotoxicol Teratol 2014;43:51–8. Loepke AW, Istaphanous GK, McAuliffe 3rd JJ, Miles L, Hughes EA, McCann JC, et al. The effects of neonatal isoflurane exposure in mice on brain cell viability, adult behavior, learning, and memory. Anesth Analg 2008;108:90–104. Palanisamy A. Maternal anesthesia and fetal neurodevelopment. Int J Obstet Anesth 2012; 21:152–62.
Deshui Yu Guangyun Sun⁎ Department of Anesthesiology, The Second People's Hospital of Yibin, Yibin, Sichuan, PR China ⁎Corresponding author at: Department of Anesthesiology, The Second People's Hospital of Yibin, No. 96 North Street, Yibin 644000, Sichuan, PR China. Tel./fax: +86 831 8255069. E-mail address: [email protected] (G. Sun).
3 June 2014