General Anesthetic
PREGNANCY RECOMMENDATION: Limited Human Data—Animal Data Suggest Low Risk
BREASTFEEDING RECOMMENDATION: No Human Data—Probably Compatible
PREGNANCY SUMMARY
Sevoflurane is teratogenic in mice, but no reports of its use in early human gestation have been located. The absence of human experience during organogenesis prevents an assessment of the risk for structural anomalies. In addition, general anesthesia usually involves the use of multiple pharmacological agents. Although no teratogenicity has been observed with other halogenated general anesthetic agents, only halothane has 1st trimester human exposure data (see Halothane). Sevoflurane has been used immediately prior to delivery, but its effect on the newborn has not been studied. However, its effect on the newborn is probably no different from other general anesthetic agents. The uterine effects of sevoflurane (relaxation and increased blood loss) also appear to be similar to other agents in this class, but the low concentrations used clinically minimize these actions (see Enflurane). All anesthetic agents can cause depression in the newborn that may last for 24 hours or more but, again, this is lessened by the low doses. The potential reproductive toxicity (spontaneous abortion and infertility) of occupational exposure to halogenated general anesthetic agents has not been adequately studied.
FETAL RISK SUMMARY
Sevoflurane, a noninflammable general anesthetic agent administered via vaporizer, is indicated for the induction and/or maintenance of anesthesia during surgery. Sevoflurane is in the same class of volatile liquid halogenated agents as desflurane, enflurane, halothane, isoflurane, and methoxyflurane. It has a lower solubility in lipids (oil:gas partition coefficient about 47–53) and blood (blood:gas partition coefficient 0.68) than halothane or isoflurane, but higher than desflurane (1). The anesthetic potency, based on the minimum alveolar anesthetic concentration (MAC), is about 50% less than that of isoflurane but about 30% more than that of desflurane (1). (Note: MAC is the concentration that causes immobility in 50% of patients exposed to a noxious stimulus such as a surgical incision; it represents the ED50[2]).
In an animal reproduction study, mice were exposed for 8 hours to sevoflurane and enflurane combined with three different concentrations of oxygen (3). Both anesthetic agents caused cleft palate, but the incidence was lower than that observed with halothane. Increasing the concentrations of oxygen lowered the incidence of the defect (3).
The teratogenic potential of sevoflurane, enflurane, and isoflurane was studied by evaluating the effect of each agent on the proliferation and differentiation of cells exiting from the G1-phase of the cell cycle (4). The theory behind the study was that normal development during embryogenesis, organogenesis, and histogenesis depended upon the proliferation and differentiative processes of cell migration (4). For example, valproate, a known human teratogen, is a potent G1-phase inhibitor of the in vitro proliferation rate at concentrations less than two times the therapeutic plasma concentration. At anesthetic concentrations less than two times the MAC, the antiproliferative potency of the three agents was isoflurane = enflurane >> sevoflurane. However, in the growth-arrested cell population, there was no specific accumulation of any cell-cycle phase and no specific effect on the G1 phase. The investigators concluded that the three agents lacked the specific in vitro characteristics of valproate (4).
In an in vitro experiment with pregnant rats, sevoflurane, halothane, and isoflurane significantly inhibited oxytocin-induced contractions of uterine smooth muscle (5).
Two reviews have concluded that, in general, inhalational anesthetics are freely transferred to fetal tissues (6,7) and, in most cases, the maternal and fetal concentrations are equivalent (7). The low molecular weight (about 200) and the presence of sevoflurane in the maternal brain support this assertion.
A 1999 case report described the use of sevoflurane for maintenance of general anesthesia during a nonobstetric surgery in a 25-year-old woman at 13 weeks’ gestation (8). Six months later, a cesarean section delivered a 2820-g female infant without abnormalities.
Two reports described the use of sevoflurane for emergency cesarean section (9,10). Although successful outcomes occurred in both cases, the former report generated several letters and a reply (11–16).
Chronic occupational exposure to anesthetic gases in operating rooms during pregnancy has raised concerns that such exposure could cause birth defects and spontaneous abortions (17). A 1988 review cited a number of studies investigating the possible association between occupational exposure to anesthetic gases and adverse pregnancy outcomes (6). The reviewer concluded that serious methodological weaknesses in these studies precluded arriving at a firm conclusion, but a slightly increased risk of miscarriage was a possibility. However, there was no evidence of an association between occupational exposure and congenital anomalies (6).
A 2004 study, however, found a significant association between maternal occupational exposure to waste anesthetic gases during pregnancy and developmental deficits in their children, including gross and fine motor ability, inattention/hyperactivity, and IQ performance (see Nitrous Oxide).
BREASTFEEDING SUMMARY
Although sevoflurane has been administered during delivery, the effects of this exposure on the infant who begins nursing immediately after birth have not been described. Sevoflurane is probably excreted into colostrum and milk as suggested by its presence in the maternal blood and its low molecular weight (about 200), but the toxic potential of this exposure for the infant is unknown. However, the risk to a nursing infant from exposure to sevoflurane via milk is probably very low (18). Halothane, another halogenated inhalation anesthetic, is classified as compatible with breastfeeding by the American Academy of Pediatrics (see Halothane).
References
1.Patel SS, Goa KL. Sevoflurane. A review of its pharmacodynamic and pharmacokinetic properties and its clinical use in general anaesthesia. Drugs 1996;51:658–700.
2.Trevor AJ, Miller RD. General anesthetics. In: Katzung BG, ed. Basic and Clinical Pharmacology. 8th ed. New York, NY: McGraw-Hill, 2001:426.
3.Natsume N, Miura S, Sugimoto S, Nakamura T, Horiuchi R, Kondo S, Furukawa H, Inagaki S, Kawai T, Yamada M, Arai T, Hosoda R. Teratogenicity caused by halothane, enflurane, and sevoflurane, and changes depending on O2concentration (abstract). Teratology 1990;42:30A.
4.O’Leary G, Bacon CL, Odumeru O, Fagan C, Fitzpatrick T, Gallagher HC, Moriarty DC, Regan CM. Antiproliferative actions of inhalational anesthetics: comparisons to the valproate teratogen. Int J Devl Neurosci 2000;18:39–45.
5.Yamakage M, Tsujiguchi N, Chen X, Kamada Y, Namiki A. Sevoflurane inhibits contraction of uterine smooth muscle from pregnant rats similarly to halothane and isoflurane. Can J Anesth 2002;49:62–6.
6.Friedman JM. Teratogen update: anesthetic agents. Teratology 1988;37:69–77.
7.Kanto J. Risk–benefit assessment of anaesthetic agents in the puerperium. Drug Saf 1991;6:285–301.
8.Kanazawa M, Kinefuchi Y, Suzuki T, Fukuyama H, Takiguchi M. The use of sevoflurane anesthesia during early pregnancy. Tokai J Exp Clin Med 1999;24:53–5.
9.Schaut DJ, Khona R, Gross JB. Sevoflurane inhalation induction for emergency cesarean section in a parturient with no intravenous access. Anesthesiology 1997;86:1392–4.
10.Que JC, Lusaya VO. Sevoflurane induction for emergency cesarean section in a parturient in status asthmaticus. Anesthesiology 1999;90:1475–6.
11.Klafta JM. The practice of using sevoflurane inhalation induction for emergency cesarean section and a parturient with no intravenous access. Anesthesiology 1998;88:275.
12.Bhavani-Shankar K, Camann WR. The practice of using sevoflurane inhalation induction for emergency cesarean section and a parturient with no intravenous access. Anesthesiology 1998;88:275–6.
13.Sitzman BT. The practice of using sevoflurane inhalation induction for emergency cesarean section and a parturient with no intravenous access. Anesthesiology 1998;88:276.
14.Gambling DR, Reisner LS. The practice of using sevoflurane inhalation induction for emergency cesarean section and a parturient with no intravenous access. Anesthesiology 1998;88:276–7.
15.Maltby JR. The practice of using sevoflurane inhalation induction for emergency cesarean section and a parturient with no intravenous access. Anesthesiology 1998;88:277–8.
16.Gross JB. The practice of using sevoflurane inhalation induction for emergency cesarean section and a parturient with no intravenous access. Anesthesiology 1998;88:278.
17.Corbett TH. Cancer and congenital anomalies associated with anesthetics. Ann NY Acad Sciences 1976;271:58–66.
18.Spigset O. Anaesthetic agents and excretion in breast milk. Acta Anaesthesiol Scand 1994;38:94–103.