|Year : 2013 | Volume
| Issue : 2 | Page : 77-83
Long-term psychosocial behavioral outcomes in children following anesthesia: A comparison of the effects of general versus regional anesthesia on term infants delivered by elective cesarean section
Aouni Alameddine1, Raymond Kamel2, Francis Leclerc3, Laurent Storme4, Mohamad K Ramadan5, Zouher Naja6, Mariam El-Rajab1
1 Department of Pediatrics, Makassed General Hospital, Beirut, Lebanon
2 Department of Pediatrics, Saint George University Hospital, Beirut, Lebanon
3 Pediatric Intensive Care Unit, Jeanne de Flandre Hospital, Lille, France
4 Department of Perinatal Medicine, Jeanne de Flandre Hospital, Lille, France
5 Maternofetal Unit, Makassed General Hospital, Beirut, Lebanon
6 Department of Anesthesia and Pain Medicine, Makassed General Hospital, Beirut, Lebanon
|Date of Web Publication||19-Dec-2013|
Department of Pediatrics, Makassed General Hospital, Ouzai Street, Beirut
Source of Support: The education committee of our hospital supported the survey by means of an educational grant, Conflict of Interest: None
Background: Data on the effects of general anesthesia on the fetal and neonatal brain are limited. Animal studies demonstrated that anesthetic agents leave their consequences in the form of learning and memory deficits. The effects of propofol on the fetal neurodevelopment are not clear yet.
Materials and Methods: This is a telephone-based questionnaire survey that addressed the effect of general anesthesia by propofol during cesarean section at term with no perinatal complications on the psychosocial behavior of children at 8-10 years of age compared with children having same characteristics except for delivery under neuraxial anesthesia using the Pediatric Symptom Checklist as a score.
Results: A total of 187 children were born at term between January 1, 2002 and December 31, 2004 with no perinatal distress under induction of general anesthesia by propofol. 66 children (35.3%) were lost to follow-up and parents of two children (1.1%) refused to participate. A total of 189 children were included in the study: 119 were born by cesarean section under general anesthesia and 70 were born by cesarean section under neuraxial block. The incidence of psychosocial behavior impairment at 8-10 years of age was not found to be affected by the mode of anesthesia during delivery by cesarean section nor by neonatal nor parental characteristics.
Conclusion: Exposure to propofol as an induction agent for general anesthesia or cesarean section does not seem to increase the psychosocial behavior disorder development risk at 8-10 years of age.
Keywords: Behavior, cesarean section, general anesthesia, obstetrical anesthesia, propofol
|How to cite this article:|
Alameddine A, Kamel R, Leclerc F, Storme L, Ramadan MK, Naja Z, El-Rajab M. Long-term psychosocial behavioral outcomes in children following anesthesia: A comparison of the effects of general versus regional anesthesia on term infants delivered by elective cesarean section. J Obstet Anaesth Crit Care 2013;3:77-83
|How to cite this URL:|
Alameddine A, Kamel R, Leclerc F, Storme L, Ramadan MK, Naja Z, El-Rajab M. Long-term psychosocial behavioral outcomes in children following anesthesia: A comparison of the effects of general versus regional anesthesia on term infants delivered by elective cesarean section. J Obstet Anaesth Crit Care [serial online] 2013 [cited 2019 Dec 13];3:77-83. Available from: http://www.joacc.com/text.asp?2013/3/2/77/123300
| Introduction|| |
Pre- and perinatal-exposure to drugs and medications and has been implicated in a number of developmental, behavioral and psychiatric outcomes in children.  These include neuronal apoptosis during synaptogenesis, suppression of neurogenesis, morphologically abnormal synapse formation, altered dendritic spinogenesis, impaired hippocampal long-term potentiation, deformation of neuronal and astroglial cytoskeletal protein, neuronal mitochondrial dysfunction, abnormal intra-neuronal calcium homeostasis and aberrant cell cycle re-entry during mitosis. 
Animal studies have shown that anesthetic agents influence early brain development by altering both the anatomical organization of the brain as well as inducing functional consequences in the form of learning and memory deficits. Although data on the fetal brain are limited, most animal studies indicate that the developing fetal brain is at risk from maternal anesthesia especially during the second trimester. Inhalational anesthetics are frequently implicated, but at this point it is not known if propofol has similar widespread effects on fetal neurodevelopment.  Our aim was to assess the psychosocial outcome of children who were born by cesarean section under propofol as an induction agent for general anesthesia, since the issue of general anesthetic effects on infants is currently one of the most prominent subjects.
| Materials and Methods|| |
The ethical approval was granted by the Institutional Review Board (IRB) committee of our institution.
We carried a telephone-based questionnaire survey of children born at term by cesarean section under induction of general anesthesia by propofol followed by maintenance with a volatile anesthetic (sevoflurane) between January 1, 2002 and December 31, 2004 concerning their psychosocial behavior development. All children who were born full-term by elective "repeat" cesarean section with no history of any fetal or neonatal distress were included in our survey. Infants of mothers with a history of exposure to anesthetics during pregnancy as well as infants who were a product of multiple-gestation were excluded. In addition, we excluded children who were exposed to general or local anesthesia for any reason before the time of telephonic interview.
We compared these children to children born by elective "repeat" cesarean section at term under neuraxial anesthesia and product of single gestation and with no history of any fetal distress or exposure to anesthetics during pregnancy. We did not encounter any severe hemodynamic side effects of anesthesia in either group.
We used the Pediatric Symptom Checklist (PSC) [Table 1]  to assess the cognitive, emotional and behavioral development in the included children. The parents were asked to answer the 35-item PSC questionnaire. Items were rated as "Never," "Sometimes," or "Often" and Scored 0, 1 and 2, respectively. The total scores were calculated by adding together the score for each of the 35 items. A cut-off Score of 28 or higher indicates psychological impairment. Blank items were ignored (i.e., Score equals 0). If four or more items were left blank, the questionnaire was considered invalid.
We also assessed the effects of maternal age at childbirth, complications of pregnancy, parental educational level achieved as by the national school system, infant's sex and birth weight on the PSC score.
Statistical analyzes by chi-square test were performed using the Statistical Package for the Social Sciences software (version 16, SPSS, Chicago, IL).
The ethical approval was granted by the IRB committee of our institution.
| Results|| |
After we reviewed the medical record charts of our institution, we succeeded in contacting parents of 121 children (64.7%) born full-term by elective cesarean section under general anesthesia where Propofol was used for induction at a dose of 2.5 mg/kg followed by an intubation and maintenance with a volatile anesthetic out of a total of 272 medical records eligible for inclusion. Parents of 66 children (35.3%) were lost to contact and parents of two children (1.1%) refused to participate in our survey. Hence, 119 children (63.6%) participated in our survey [Figure 1].
|Figure 1: Children born by cesarean section eligible for inclusion in the study|
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93 mothers (76.9%) were 15 to 34 years old at the time of delivery, whereas 28 mothers (23.1%) were 35 year old or above. The majority of mothers and fathers were high school graduates as shown in [Table 2]. Our data showed that 55.4% of these children were males and 44.6% females and the majority of children had a birth weight of 2500 g or more. Most of the children were born during the 37 th and 38 th post-conceptual week (35.8 and 25% respectively) versus 21.7 and 15% born in the 39 th and 40 th post-conceptual weeks respectively. 104 of our children (87.4%) scored below 28 in the PSC versus 15 children (12.6%) Scoring 28 or above [Table 3].
On the other hand, we were able to contact parents of 70 children (82.3%) born by cesarean section at term under neuraxial anesthesia with no perinatal complications and product of a singleton pregnancy out of a total of 85 children [Figure 1].
The details regarding educational levels of the parents are shown in [Table 2]. All infants weighed 2500 g and 80% of them were born during the 37 th and 38 th post-menstrual week. Almost 11.5% of these children had a PSC Score of 28 or more at 8 to 10 years of age [Table 3].
The parental educational levels, maternal age at childbirth, complications of pregnancy, child sex, birth weight and gestational age were not found to increase the risk of having a PSC score higher than or equal to 28 with non-significant P values in both groups [Table 4].
|Table 4: Effects of demographic data on the pediatric symptom checklist scores|
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| Discussion|| |
The main finding of our work, which was a telephone-based questionnaire survey, was that the use of propofol for induction of general anesthesia for cesarean delivery at term is not linked to an increased risk of a psychosocial dysfunction at 8-10 years of age when compared with neuraxial anesthesia.
Growth and development of the central nervous system (CNS) in mammals involve complex cellular processes including neurogenesis, differentiation into specialized cell subspecies, migration of cells into their final destination in the CNS, synaptogenesis with connection formation and axonal myelination. These processes vary significantly in duration and timing, relative to gestational age, among different mammalian species, in accordance with their life expectancy. 
Laboratory researches have confirmed that general anesthetics cause increased neuronal apoptosis ,,,, and changes to the morphology of dendritic spines in the developing animal brains. ,, Concerns of general anesthesia are highest during the organogenesis phase in early pregnancy. However, growth and maturation of the brain and the neurologic system do not cease at birth. The changes are anesthetic-dose dependent and there is a window when the brain is most vulnerable.  In humans, synaptogenesis starts during the third post-conceptual trimester and rapid brain growth continues for up to 2-3 years of life. 
Several laboratory works on neonatal animal models, such as the 7-day old mouse and rat, demonstrate that anesthetic drug administration was linked to an increased normal apoptotic neuronal degeneration. This phenomenon has led to a controversy about the late consequences of pediatric anesthesia. ,,,,,, Laboratory findings in 7-day old rodents provide evidence for human susceptibility to anesthesia-induced neurotoxicity from the third trimester of pregnancy up to the 2 nd year of life. ,
In our institution, the general anesthetic used for induction of anesthesia for cesarean delivery is propofol at a loading dose of 2.5 mg/kg, knowing that it is an off-label use. Midazolam is given only after delivery of the fetus. The effects of propofol administration on neuronal survival and neurocognitive performance have not been formally studied neither during delivery nor in young children. Newborns delivered within 5-14 min of induction of anesthesia by propofol for cesarean section at term showed satisfactory Apgar scores and Neurologic Adaptive Capacity Scores and umbilical blood gas analysis; a prolonged duration of induction of anesthesia by this agent resulted in a poor neonatal Neurologic and Adaptive Capacity Scores.  However, propofol sedation for 48 h in a pregnant patient with intracerebral hemorrhage did not lead to any measurable adverse effects in her newborn after emergency cesarean delivery.  Similarly, experiments on rats demonstrated that 4-h exposure to propofol at clinically relevant doses had little or no in vitro effect on the viability of the neural progenitor cells or their proliferation. 
We performed a thorough Cochrane database review and research. We could not find any review concerning the late neurobehavioral effects of induction of general anesthesia with propofol during cesarean section or the effect of propofol specifically as an anesthetic induction agent for cesarean delivery in humans.
In a study done by Fredriksson et al. showed that propofol increases neurodegeneration ending with an adult behavioral and learning impairment in a dose-dependent manner in 10-day old mice.  Although neonatal exposure to propofol 10 mg/kg by subcutaneous route did not lead to neurological sequelae, increased neonatal neurodegeneration and disruption of spontaneous activity and learning in adult mice were observed after neonatal exposure to propofol 60 mg/kg. However, a minimal effective dose of propofol for causing a significant neuroapoptosis response (50 mg/kg) has been found to be approximately one-fourth the dose required to induce surgical planes of anesthesia in infant mice,  whereas only 25 mg/kg of propofol by intraperitoneal route induced neurodegeneration in the cortex and thalamus in the developing 7-day old rat brain. This was secondary to an over expression of tumor necrosis factor leading to the activation of caspase-3.  Several investigators noted dose-dependent neuronal structural changes after propofol exposure, ,,, as well as a long-term impairment of higher-order CNS functions  using in vitro preparations of neuronal cell cultures from immature chicks and rats.
All experimental studies concerning the long-term neurologic effects of general anesthetics are performed on animal models, particularly on rodents. This makes it difficult to extrapolate the results on humans because the duration and the aspect of growth and development of the CNS vary greatly between these two species. For example, neurogenesis in rodents brains starts on the 9 th day until the 22 nd post-conceptual day, neuronal migration starts on the 12 th post-conceptual day and ends on the 3 rd day of life (which accounts for the 25 th post-conceptual day) and synaptogenesis starts at birth until the age of 2 weeks; whereas in humans, neurogenesis occurs between the 10 th and the 23 rd post-conceptual week, neuronal migration between the 14 th and the 29 th post-conceptual week and synaptogenesis between the 30 th post-conceptual week and the 2 nd year of life. 
Sprung et al. concluded that children exposed to general anesthesia by sodium thiopental, ketamine and potent inhalational anesthetics or regional anesthesia during cesarean delivery are not more likely to develop learning disability compared with those delivered by the vaginal route under neuraxial anesthesia. In the other hand, they found that the risk of learning disability was lower in children born by cesarean section under neuraxial anesthesia.  They did not study the effect of delivery under propofol as a general anesthetic. This finding may be explained by the fact that cesarean delivery under neuraxial anesthesia alleviates the stress of normal active labor and delivery on the fetal nervous system.
Dailland et al. demonstrated that propofol crosses the placenta by concentrations in umbilical venous blood ranging between 0.13 and 1.37 μg/ml. The ratio of the drug concentration in umbilical venous blood at delivery to that in maternal blood ranged between 0.7 and 0.76. However, the mean propofol concentration in blood samples taken via a heel prick 2 h after birth in 8 newborns was low and represented 10% of the corresponding umbilical cord artery concentration at time of delivery and was found to be cleared rapidly from the neonatal circulation.  A study conducted by Celleno et al. in 1989 concluded that newborn children examined 1 h after birth, after maternal anesthesia with propofol showed depression in an alert state, pinprick and placing reflexes and mean decremental count in Moro and light reflexes. There was generalized irritability in 25% of the studied newborns. This depression was not seen at 4 h of life.  This fact may be explained by the transplacental crossing of the anesthetic agent and the relatively high umbilical venous blood concentrations in the immediate postnatal circulation with rapid elimination of the drug within the first 2 h of life. The safety of propofol regarding the psychosocial development and behavior in childhood as shown by our study may be explained by the rapid clearance of propofol from the neonatal circulation within 2 h after birth, leading to a limited exposure of the brain and CNS to this anesthetic agent.
We used the PSC which is a screening tool for psychosocial behavior disorder has reliability reaching 84%, with 88-92% sensitivity and a specificity reaching 99%. ,,,
Jellinek et al. demonstrated that the overall prevalence rate of psychosocial dysfunction as measured by the PSC in school-aged children was 13%,  which is comparable to our findings.
Our work was limited by several factors. Both the sample and the control group size were small. The psychosocial behavior development was assessed by a screening tool and not by a thorough examination and clinical assessment.
| Conclusion|| |
Our results suggest that a brief perinatal exposure to propofol as an induction agent of general anesthesia at a dose of 2.5 mg/kg during cesarean delivery does not increase the risk of psychosocial behavior disorder compared with neuraxial anesthesia exposure. Parental demographic data, sex and birth weight of the children were not found to have an effect on the psychosocial behavior development at school-age. To the best of our knowledge, this is the first study to assess the long-term psychosocial behavior development effects of propofol as an induction agent for general anesthesia for cesarean section on the later school-aged period. Clinical in-vivo and in vitro studies in humans, as well as in primates, are needed to assess the effect of the dosing and the duration of exposure of general anesthetic on the developing brain.
| References|| |
|1.||Bresnahan M, Susser E. Belated concerns and latent effects: The example of schizophrenia. Epidemiology 2007;18:583-4. |
|2.||Palanisamy A. Maternal anesthesia and fetal neurodevelopment. Int J Obstet Anesth 2012;21:152-62. |
|3.||Jellinek MS, Murphy JM, Burns BJ. Brief psychosocial screening in outpatient pediatric practice. J Pediatr 1986;109:371-8. |
|4.||Dobbing J. The later development of the brain and its vulnerability. In: Davis JA, Dobbing J, editors. Scientific Foundations of Paediatrics. London, UK: Heinemann Medical; 1991. p. 744-59. |
|5.||Fredriksson A, Pontén E, Gordh T, Eriksson P. Neonatal exposure to a combination of N-methyl-D-aspartate and gamma-aminobutyric acid type A receptor anesthetic agents potentiates apoptotic neurodegeneration and persistent behavioral deficits. Anesthesiology 2007;107:427-36. |
|6.||Jevtovic-Todorovic V, Hartman RE, Izumi Y, Benshoff ND, Dikranian K, Zorumski CF, et al. Early exposure to common anesthetic agents causes widespread neurodegeneration in the developing rat brain and persistent learning deficits. J Neurosci 2003;23:876-82. |
|7.||Wise-Faberowski L, Zhang H, Ing R, Pearlstein RD, Warner DS. Isoflurane-induced neuronal degeneration: An evaluation in organotypic hippocampal slice cultures. Anesth Analg 2005;101:651-7. |
|8.||Yon JH, Daniel-Johnson J, Carter LB, Jevtovic-Todorovic V. Anesthesia induces neuronal cell death in the developing rat brain via the intrinsic and extrinsic apoptotic pathways. Neuroscience 2005;135:815-27. |
|9.||Liang G, Ward C, Peng J, Zhao Y, Huang B, Wei H. Isoflurane causes greater neurodegeneration than an equivalent exposure of sevoflurane in the developing brain of neonatal mice. Anesthesiology 2010;112:1325-34. |
|10.||Briner A, De Roo M, Dayer A, Muller D, Habre W, Vutskits L. Volatile anesthetics rapidly increase dendritic spine density in the rat medial prefrontal cortex during synaptogenesis. Anesthesiology 2010;112:546-56. |
|11.||De Roo M, Klauser P, Briner A, Nikonenko I, Mendez P, Dayer A, et al. Anesthetics rapidly promote synaptogenesis during a critical period of brain development. PLoS One 2009;4:e7043. |
|12.||Vutskits L, Gascon E, Tassonyi E, Kiss JZ. Effect of ketamine on dendritic arbor development and survival of immature GABAergic neurons in vitro. Toxicol Sci 2006;91:540-9. |
|13.||Davidson AJ. Anesthesia and neurotoxicity to the developing brain: The clinical relevance. Paediatr Anaesth 2011;21:716-21. |
|14.||Olney JW, Young C, Wozniak DF, Jevtovic-Todorovic V, Ikonomidou C. Do pediatric drugs cause developing neurons to commit suicide? Trends Pharmacol Sci 2004;25:135-9. |
|15.||Soriano SG, Anand KJ, Rovnaghi CR, Hickey PR. Of mice and men: Should we extrapolate rodent experimental data to the care of human neonates? Anesthesiology 2005;102:866-8. |
|16.||Todd MM. Anesthetic neurotoxicity: The collision between laboratory neuroscience and clinical medicine. Anesthesiology 2004;101:272-3. |
|17.||Davidson A, Soriano S. Does anaesthesia harm the developing brain-Evidence or speculation? Paediatr Anaesth 2004;14:199-200. |
|18.||Jevtovic-Todorovic V. General anesthetics and the developing brain: Friends or foes? J Neurosurg Anesthesiol 2005;17:204-6. |
|19.||Olney JW, Young C, Wozniak DF, Ikonomidou C, Jevtovic-Todorovic V. Anesthesia-induced developmental neuroapoptosis. Does it happen in humans? Anesthesiology 2004;101:273-5. |
|20.||Soriano SG, Loepke AW. Let′s not throw the baby out with the bath water: Potential neurotoxicity of anesthetic drugs in infants and children. J Neurosurg Anesthesiol 2005;17:207-9. |
|21.||Yau G, Gin T, Ewart MC, Kotur CF, Leung RK, Oh TE. Propofol for induction and maintenance of anaesthesia at caesarean section. A comparison with thiopentone/enflurane. Anaesthesia 1991;46:20-3. |
|22.||Loepke AW, Soriano SG. An assessment of the effects of general anesthetics on developing brain structure and neurocognitive function. Anesth Analg 2008;106:1681-707. |
|23.||Palanisamy A, Moller L, Boyd J, Crosby G, Culley DJ. Effect of propofol on neural stem/progenitor cells in vitro. Presented at the American Society of Anesthesiologists, Annual Meeting, San Diego, CA, USA; 2010. |
|24.||Cattano D, Young C, Straiko MM, Olney JW. Subanesthetic doses of propofol induce neuroapoptosis in the infant mouse brain. Anesth Analg 2008;106:1712-4. |
|25.||Pesiæ V, Milanoviæ D, Taniæ N, Popiæ J, Kanazir S, Jevtoviæ-Todoroviæ V, et al . Potential mechanism of cell death in the developing rat brain induced by propofol anesthesia. Int J Dev Neurosci 2009;27:279-87. |
|26.||Vutskits L, Gascon E, Tassonyi E, Kiss JZ. Clinically relevant concentrations of propofol but not midazolam alter in vitro dendritic development of isolated gamma-aminobutyric acid-positive interneurons. Anesthesiology 2005;102:970-6. |
|27.||Al-Jahdari WS, Saito S, Nakano T, Goto F. Propofol induces growth cone collapse and neurite retractions in chick explant culture. Can J Anaesth 2006;53:1078-85. |
|28.||Honegger P, Matthieu JM. Selective toxicity of the general anesthetic propofol for GABAergic neurons in rat brain cell cultures. J Neurosci Res 1996;45:631-6. |
|29.||Spahr-Schopfer I, Vutskits L, Toni N, Buchs PA, Parisi L, Muller D. Differential neurotoxic effects of propofol on dissociated cortical cells and organotypic hippocampal cultures. Anesthesiology 2000;92:1408-17. |
|30.||Sprung J, Flick RP, Wilder RT, Katusic SK, Pike TL, Dingli M, et al. Anesthesia for cesarean delivery and learning disabilities in a population-based birth cohort. Anesthesiology 2009;111:302-10. |
|31.||Dailland P, Cockshott ID, Lirzin JD, Jacquinot P, Jorrot JC, Devery J, et al. Intravenous propofol during cesarean section: Placental transfer, concentrations in breast milk, and neonatal effects. A preliminary study. Anesthesiology 1989;71:827-34. |
|32.||Celleno D, Capogna G, Tomassetti M, Costantino P, Di Feo G, Nisini R. Neurobehavioural effects of propofol on the neonate following elective caesarean section. Br J Anaesth 1989;62:649-54. |
|33.||Jellinek MS, Murphy JM, Little M, Pagano ME, Comer DM, Kelleher KJ. Use of the Pediatric Symptom Checklist to screen for psychosocial problems in pediatric primary care: A national feasibility study. Arch Pediatr Adolesc Med 1999;153:254-60. |
|34.||Jellinek MS, Murphy JM, Robinson J, Feins A, Lamb S, Fenton T. Pediatric Symptom Checklist: Screening school-age children for psychosocial dysfunction. J Pediatr 1988;112:201-9. |
|35.||Murphy JM, Ichinose C, Hicks RC, Kingdon D, Crist-Whitzel J, Jordan P, et al. Utility of the Pediatric Symptom Checklist as a psychosocial screen to meet the federal Early and Periodic Screening, Diagnosis, and Treatment (EPSDT) standards: A pilot study. J Pediatr 1996;129:864-9. |
[Table 1], [Table 2], [Table 3], [Table 4]