General Anesthetic
PREGNANCY RECOMMENDATION: Limited Human Data—Animal Data Suggest Low Risk
BREASTFEEDING RECOMMENDATION: No Human Data—Probably Compatible
PREGNANCY SUMMARY
Enflurane is teratogenic in mice but not in rats. No reports of its use early in 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). The potential reproductive toxicity (spontaneous abortion and infertility) of occupational exposure to halogenated general anesthetic agents has not been adequately studied.
FETAL RISK SUMMARY
Enflurane, a nonflammable general inhalation anesthetic agent administered via vaporizer, is indicated for the induction and/or maintenance of anesthesia during surgery. It also provides analgesia for vaginal delivery and, in low concentrations, is used to supplement other general anesthetic agents during delivery by cesarean section. Enflurane is in the same class of volatile liquid halogenated agents as desflurane, halothane, isoflurane, methoxyflurane, and sevoflurane. It is closely related chemically to desflurane and isoflurane (1). The blood–gas partition coefficient is 1.9 (1). This is higher (i.e., increased solubility in blood) than the value for either isoflurane (1.46) or desflurane (0.42) (see Desflurane or Isoflurane).
Studies in animals have not revealed evidence of carcinogenic or mutagenic effects. Reproduction studies, conducted in rats and rabbits at doses up to four times the human dose, revealed no evidence of impaired fertility or fetal harm (1).
In a 1981 study with mice, chronic exposure to subanesthetic and anesthetic concentrations of enflurane was evaluated. High exposures, about 100 times greater than the level of human occupational exposure in unscavenged operating rooms, were associated with minor developmental variations (lumbar ribs and increased pelvic cavitation) and defects (cleft palate, minor skeletal and visceral anomalies). The effects were greater than those observed with methoxyflurane, but less than those with halothane (2).
In a second study by the authors of the above report, the effects of four general anesthetic agents were compared in pregnant rats (3). The doses and agents used were nitrous oxide (75%; 0.55 MAC), enflurane (1.65%; 0.75 MAC), halothane (0.8%; 0.75 MAC), and isoflurane (1.05%; 0.75 MAC). (Note: The minimum alveolar anesthetic concentration [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 (4).) Each agent was administered for 6 hours on each of three consecutive days in one of three gestational periods: pregnancy days 8–10, 11–13, or 14–16. Compared with controls, significantly decreased maternal weight gain was observed in three of the groups (nitrous oxide, isoflurane, and enflurane) after exposure on days 14–16. Exposure on those days resulted in significantly decreased fetal weight in all four groups, and when exposure occurred on days 8–10 in three groups (all except nitrous oxide). Nitrous oxide exposure during days 14–16 resulted in significant increases in total fetal wastage and resorptions (threefold increases). However, no major or minor teratogenic effects were observed in any of the groups (3).
The teratogenic potential of isoflurane, enflurane, and sevoflurane 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 (5). The theory behind the study was that normal development during embryogenesis, organogenesis, and histogenesis depended upon the proliferation and differentiative processes of cell migration (5). 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 (5).
In a 1990 study, mice were exposed for 8 hours to sevoflurane and enflurane combined with three different concentrations of oxygen (6). 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 (6).
Reviews have concluded that, in general, inhalational anesthetics are freely transferred to fetal tissues (7,8) and, in most cases, the maternal and fetal concentrations are equivalent (8). The low molecular weight (about 185) and the presence of enflurane in the maternal brain support this assertion.
Two reports described the use of enflurane in 100 women for anesthesia for cesarean section (9,10). No increase in newborn adverse effects was observed.
A small 1983 study compared the neonatal outcomes in four groups (10 patients each) of women receiving general anesthesia for cesarean section: 50% nitrous oxide and 50% oxygen either alone, or combined with 0.5% halothane, 1.0% enflurane, or 0.75% isoflurane (11). One newborn had an Apgar score less than 7 at 1 minute (enflurane group), but all newborns in all groups had scores of 7 or greater at 5 minutes. There were no significant differences between the groups in neonatal neurobehavior assessment 2–4 hours after delivery or in maternal or umbilical blood gas analysis at delivery (11).
In a 1977 in vitro study, enflurane was shown to have a statistically significant depressive effect on myometrial strips from nongravid and gravid uteri (12). Three anesthetic agents, isoflurane, enflurane, and halothane, were studied at three concentrations (0.5, 1.0, and 1.5 MAC). The amount of depression was dose-related for each agent and was similar with all agents (12).
In a study to determine if pregnancy decreases the MAC, enflurane and halothane were administered to 16 women (8 with each agent) scheduled for pregnancy termination at 8–13 weeks’ gestation (13). A comparison group of 16 nonpregnant women undergoing laparoscopic sterilization received either enflurane or halothane (8 in each group). In pregnant women, the median MAC of 1.15 volume% (range 0.95–1.25) was less than that in nonpregnant women, 1.65% volume% (range 1.45–1.75) (p = 0.0007). The percentage decrease (95% confidence interval) for pregnant women was 30% (24%–36%). Similar results were found with halothane (13).
Chronic occupational exposure to anesthetic gases in operating rooms during pregnancy has raised concerns that such exposure could cause birth defects and spontaneous abortions (14). The concentration of enflurane in an operating-room environment was stated to 5–46 parts per million (ppm) near the anesthesiologist and 1–8 ppm near the surgeon. A 1988 review cited a number of studies investigating the possible association between occupational exposure to anesthetic gases and adverse pregnancy outcomes (7). 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 (7).
In a 1982 study, the infants of mothers who had received analgesia before vaginal delivery consisting of either enflurane, nitrous oxide (both mixed with oxygen), or no inhalation agent were evaluated for neurobehavior during the first 24 hours (15). The infants were tested with the Neurologic and Adaptive Capacity Score at 15 minutes, 2 hours, and 24 hours, and with the Early Neonatal Neurobehavioral Scale at 2 and 24 hours. For all groups, scores were the lowest at 2 hours, but no significant differences were measured between the groups (15).
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).
Enflurane has been used immediately prior to delivery for analgesia and anesthesia. This use does not appear to affect the newborn any differently than other general anesthetic agents. The uterine effects of enflurane (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 (16). 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.
BREASTFEEDING SUMMARY
Although enflurane has been administered during labor and delivery, the effects of this exposure on the infant that begins nursing immediately after birth have not been described. Enflurane is probably excreted into colostrum and milk as suggested by its presence in the maternal blood and its low molecular weight (about 185), but the toxic potential of this exposure for the infant is unknown. However, the risk to a nursing infant from exposure to enflurane via milk is probably very low (17,18). Another halogenated inhalation anesthetic, halothane, is classified as compatible with breastfeeding by the American Academy of Pediatrics (see Halothane).
References
1.Product information. Ethrane. Abbott Laboratories (NZ), 1999.
2.Wharton RS, Mazze RI, Wilson AI. Reproduction and fetal development in mice chronically exposed to enflurane. Anesthesiology 1981;54:505–10.
3.Mazze RI, Fujinaga M, Rice SA, Harris SB, Baden JM. Reproductive and teratogenic effects of nitrous oxide, halothane, isoflurane, and enflurane in Sprague-Dawley rats. Anesthesiology 1986;64:339–44.
4.Trevor AJ, Miller RD. General anesthetics. In: Katzung BG, ed. Basic and Clinical Pharmacology. 8th ed. New York, NY: McGraw-Hill, 2001:426.
5.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 Dev Neurosci 2000;18:39–45.
6.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 O2 concentration (abstract). Teratology 1990;42:30A.
7.Friedman JM. Teratogen update: anesthetic agents. Teratology 1988;37:69–77.
8.Kanto J. Risk-benefit assessment of anaesthetic agents in the puerperium. Drug Saf 1991;6:285–301.
9.Coleman AJ, Downing JW. Enflurane anesthesia for cesarean section. Anesthesiology 1975;43:354–7.
10.Dick W, Knoche E, Traub E. Clinical investigations concerning the use of Ethrane for cesarean section. J Perinat Med 1979;7:125–33.
11.Warren TM, Datta S, Ostheimer GW, Naulty JS, Weiss JB, Morrison JA. Comparison of the maternal and neonatal effects of halothane, enflurane, and isoflurane for cesarean section. Anesth Analg 1983;62:516–20.
12.Munson ES, Embro WJ. Enflurane, isoflurane, and halothane and isolated human uterine muscle. Anesthesiology 1977;46:11–4.
13.Chan MTV, Mainland P, Gin T. Minimum alveolar concentration of halothane and enflurane are decreased in early pregnancy. Anesthesiology 1996;85:782–6.
14.Corbett TH. Cancer and congenital anomalies associated with anesthetics. Ann NY Acad Sci 1976;271:58–66.
15.Stefani SJ, Hughes SC, Shnider SM, Levinson G, Abboud TK, Henriksen EH, Williams V, Johnson J. Neonatal neurobehavioral effects of inhalation analgesia for vaginal delivery. Anesthesiology 1982;56:351–5.
16.Quail AW. Modern inhalational anaesthetic agents: a review of halothane, isoflurane and enflurane. Med J Aust 1989;150:95–102.
17.Lee JJ, Rubin AP. Breast feeding and anaesthesia. Anaesthesia 1993;48:616–25.
18.Spigset O. Anaesthetic agents and excretion in breast milk. Acta Anaesthesiol Scand 1994;38:94–103.