General Anesthetic
PREGNANCY RECOMMENDATION: Limited Human Data—Animal Data Suggest Low Risk
BREASTFEEDING RECOMMENDATION: No Human Data—Probably Compatible
PREGNANCY SUMMARY
Isoflurane was not teratogenic in three animal species at doses that did not cause maternal toxicity. No reports of its use early in human gestation have been located. The absence of human experience during organogenesis prevents a complete 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 two other halogenated general anesthetic agents (halothane and methoxyflurane), only halothane has 1st trimester human exposure data. Isoflurane has been used immediately prior to delivery for analgesia and anesthesia. This use does not appear to affect the newborn any differently from other general anesthetic agents. The uterine effects of isoflurane (relaxation and increased blood loss) also appear to be similar to other agents in this class. All anesthetic agents can cause depression in the newborn that may last for 24 hours or more. The potential reproductive toxicity (spontaneous abortion [SAB] and infertility) of occupational exposure to isoflurane has not been studied but is a concern based on the exposure concentration found in one study. Further, occupational exposure to nitrous oxide was also measured in that study, and indicated that the nurses were exposed to both nitrous oxide and volatile anesthetic agents at the same time.
FETAL RISK SUMMARY
The nonflammable general anesthetic isoflurane is in the same class of volatile liquid halogenated agents such as desflurane, enflurane, halothane, methoxyflurane, and sevoflurane. It is closely related to desflurane and enflurane. The only difference between isoflurane and desflurane is the presence of a chlorine atom in isoflurane instead of a fluorine atom. This small difference, however, produces marked pharmacokinetic and clinical effects. The potency of isoflurane is five times that of desflurane, the blood–gas partition coefficient is increased (i.e., increased solubility in blood) (1.46 vs. 0.42), tissue solubility is increased (brain–blood partition coefficient 1.6 vs. 1.3), and recovery from anesthesia is slower (1).
In an animal reproductive study, mean anesthetic concentrations (about 1.6%) of isoflurane were administered to male and female rats for 5-day intervals up to 15 days before pairing (2). No adverse effects on mating and fertility indices were observed. Studies for structural anomalies were conducted in pregnant rats and rabbits in the same way. Three groups of rats received mean anesthetic doses of 1.6%–1.7% for 5-day intervals between day 1 and day 15 of gestation, whereas three groups of rabbits received mean doses of 2.3% for 4- or 5-day intervals between day 6 and 18 of gestation. No congenital malformations related to the exposures were found in either animal species (2). In the third segment of this study, pregnant rats were exposed to isoflurane 1.74% for 1 hour/day on gestation days 15–20. Maternal weight gain was significantly less in the exposed group, and fetal survival was also decreased (2).
Three dose-levels of isoflurane were administered in a reproduction study with pregnant mice: trace (0.006%), subanesthetic (0.06%), and light anesthetic (0.6%) (3). No adverse maternal or fetal effects were observed when the two smaller concentrations were administered for 4 hours daily on days 6–15 of pregnancy. When given the same way, the light anesthetic dose, however, resulted in significantly lower maternal weight gain. Fetal toxicity included a significant decrease in fetal weight, decreased skeletal ossification, minor hydronephrosis, and increased pelvic cavitation (3). In addition, an increased incidence of cleft palate was observed (12.1% vs. 0.75% for controls). The incidence of cleft palate also was higher than that observed in previous experiments with halothane (1.2%) or enflurane (1.9%) (3).
In a second study by the authors of the above report, the effects of four general anesthetic agents were compared in pregnant rats (4). The doses and agents used were nitrous oxide (75%; 0.55 minimum alveolar anesthetic concentration [MAC]), enflurane (1.65%; 0.75 MAC), halothane (0.8%; 0.75 MAC), and isoflurane (1.05%; 0.75 MAC). (Note: The 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 [5] ). 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 (three-fold) in total fetal wastage and resorptions. However, no major or minor teratogenic effects were observed in any of the groups (4).
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 (6). The theory behind the study was that normal development during embryogenesis, organogenesis, and histogenesis depended on the proliferation and differentiative processes of cell migration (6). For example, valproate, a known human teratogen, is a potent G1-phase inhibitor of the in vitro proliferation rate at concentrations <2 times the therapeutic plasma concentration. At anesthetic concentrations <2 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 (6).
Three anesthetic agents, isoflurane, halothane, and methoxyflurane, were administered to pregnant (near term) and nonpregnant ewes in a study designed to determine the requirement for inhaled anesthetic agents (7). The MAC was decreased in the pregnant animals in each case, 40%, 25%, and 32% less, respectively. In a 1994 study, women at 8–12 weeks’ gestation (all undergoing termination of pregnancy) were matched with women undergoing gynecologic surgery (8). The MAC was reduced by 28% in comparison with the nonpregnant controls (median end-tidal concentration 0.775% vs. 1.075%, respectively).
Two reviews concluded that, in general, inhalational anesthetics are freely transferred to fetal tissues (9,10) and, in most cases, the maternal and fetal concentrations are equivalent (10). The low molecular weight (about 185) and the presence of isoflurane in the maternal brain support this assertion. In agreement, research has demonstrated the rapid uptake of isoflurane by the fetus (11).
A 1991 case report described two liver transplant procedures, 3 days apart, in a pregnant woman at approximately 21 weeks’ gestation (12). Isoflurane was the only inhaled anesthetic agent used, although a number of other drugs were administered during the combined 24.4 hours of anesthesia. The woman eventually delivered a healthy infant by cesarean section (12).
Subanesthetic doses of isoflurane have been used for labor analgesia (13–15). A study published in 1985 compared the self-administration of isoflurane (0.75% in oxygen) or 50% nitrous oxide in oxygen given in a random sequence in 32 women (13). Isoflurane use resulted in better analgesia but increased drowsiness. The condition of the newborns was not mentioned. A 1989 study used isoflurane (0.2%–0.7%) or 30%–60% nitrous oxide (30 in each group) for labor analgesia (14). Seven percent of the newborns in both groups were depressed (1-minute Apgar scores 5–7), but all had Apgar scores of 8–10 at 5 minutes. There was also no difference in neonatal neurobehavior as measured by the Neurologic and Adaptive Capacity Scores (NACS) at 15 minutes, 2 hours, and 24 hours of age. Although specific percentages were not given, it was stated that there was no significant difference between the groups in the percentage of infants who scored 35–40 on the NACS. Mothers in the isoflurane group had higher concentrations of fluoride in their urine at 12–24 hours postpartum than those who had received nitrous oxide (36.5 vs. 23.6 µmol/L), but the fluoride blood levels were similar (<5.6 µmol/L). The fluoride urine levels in the newborns (first void) also were similar (<5.6 µmol/L) (14). In a 1993 report, 17 laboring women received alternating doses of 0.2% isoflurane plus 50% nitrous oxide/oxygen or nitrous oxide/oxygen alone, each over 1-hour intervals, for a total of 3 hours (15). Analgesia was significantly better when the women were receiving isoflurane. Progressive drowsiness was noted over the 3-hour period, but it was not considered clinically significant. The newborns were delivered vaginally and all had 1- and 5-minute Apgar scores of 8 to 10. Neurobehavior assessment was not conducted (15).
Isoflurane has been used for anesthesia during cesarean section (11,16–19). As with vaginal delivery, some degree of neonatal depression may occur as indicated by Apgar scores <7 at 1 minute (11,16–18) or an NACS <35 at 2 and 24 hours of age (16). 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 (19). One newborn had an Apgar score <7 at 1 minute (enflurane group), but all newborns in all groups had scores of ≥7 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.
In a 1977 in vitro study, isoflurane was shown to have a statistically significant depressive effect on myometrial strips from nongravid and gravid uteri (20). 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 (20). Another study also demonstrated a dose-related relaxing effect of isoflurane (0.5%, 1.0%, and 1.5%) on isolated gravid human uterine muscle (21). All doses caused a significant decrease in uterine activity, but oxytocin, in a dose similar to that used clinically, reversed the effects of the anesthetic (21). In another study, the subjective assessment of maternal blood loss and uterine relaxation was less for isoflurane than for halothane (16).
A study published in 1998 evaluated the exposure of nine nurses in a postanesthesia care unit (PACU) to exhaled isoflurane and desflurane and compared these exposures with the National Institute of Occupational Safety and Health (NIOSH)-recommended exposure limits (22). The NIOSH recommendation for volatile anesthetics (without concomitant nitrous oxide exposure) is a maximum of 2 parts per million, but has not been adopted by the Occupational Safety and Health Administration. Moreover, the recommended limit is controversial and is thought by some to be inappropriately low (22). However, a potential for reproductive risk (SAB and infertility) is thought to exist for some anesthetic agents. The study involved exposure in the PACU to exhaled anesthetic gases from 50 adult patients (isoflurane N = 19, desflurane N = 31) over an approximately 1-hour recovery time. About one-half of the patients were extubated in the PACU. Exposure was continuously measured from the shoulders (i.e., breathing-zone) of the nurses. Breathing-zone anesthetic concentrations of isoflurane and desflurane exceeded the NIOSH limits in 37% and 87% of the cases, respectively. These exposures were above the limit 12% of the time for isoflurane and 49% of the time for desflurane. The investigators listed several limitations to their study and concluded that the results might represent a “worst-case analysis” (22).
A 2004 study 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 isoflurane 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. Isoflurane 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 isoflurane via milk is probably very low (24,25). Another halogenated inhalation anesthetic, halothane, is classified as compatible with breastfeeding by the American Academy of Pediatrics (see Halothane).
References
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12.Merritt WT, Dickstein R, Beattie C, Burdick J, Klein A. Liver transplantation during pregnancy: anesthesia for two procedures in the same patient with successful outcome of pregnancy. Transplant Proc 1991;23:1996–7.
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20.Munson ES, Embro WJ. Enflurane, isoflurane, and halothane and isolated human uterine muscle. Anesthesiology 1977;46:11–4.
21.Abadir AR, Humayun SG, Calvello D, Gintautas J. Effects of isoflurane and oxytocin on gravid human uterus in vitro (abstract). Anesth Analg 1987;66:S1.
22.Sessler DI, Badgwell JM. Exposure of postoperative nurses to exhaled anesthetic gases. Anesth Analg 1998;87:1083–8.
23.Lee JJ, Rubin AP. Breast feeding and anaesthesia. Anaesthesia 1993;48:616–25.
24.Spigset O. Anaesthetic agents and excretion in breast milk. Acta Anaesthesiol Scand 1994;38:94–103.