Part 11 (2/2)
Regional techniques (spinal and epidural procedures, paracervical and pudendal blocks) result in physiologically important fetal exposure to clinically significant anesthetic levels.
Table 6.2 Frequently used anesthetic agents Frequently used anesthetic agents Agent Cla.s.s Princ.i.p.al use Benzocaine Ester Topical Bupivacaine Amide Local and epidural blocks Chloroprocaine Ester Local and epidural blocks Etidocaine Amide Epidural block Lidocaine Amide Local, epidural, and spinal blocks Mepivacaine Amide Local and epidural blocks Procaine Ester Local block Tetracaine Ester Spinal Local anesthetics have an aromatic ring with an intermediate alkyl chain with (1) an amide or (2) ester linkage. Anesthetic potency is related to protein-bound fraction, and the amount of binding determines the duration of action. Highly protein bound anesthetics are lipid soluble and readily cross the placenta (Moris.h.i.+ma et al et al., 1966; Pedersen and Finster, 1987). Malformations were not increased in frequency among offspring of women who used procaine, lidocaine, benzocaine, or tetracaine during the first trimester, and there were no adverse fetal effects when these agents were utilized at any time during pregnancy (Heinonen et al et al., 1977). No animal teratology studies of these agents have been published.
No investigations of bupivacaine, chlorprocaine or prilocaine have been published with regard to their teratogenic effects. Transient newborn neurobehavioral changes in infants whose mothers received local anesthetic agents have been reported, and vary from moderate for regional blocks (Rosenblatt et al et al., 1981; Scanlon et al et al., 1974; Standley et al et al., 1974) to minimal for epidural anesthesia on newborn behavior (Tronick et al et al., 1976).
Epinephrine Epinephrine is added to local anesthetics to prolong their action. Following first trimester exposure there was a significantly increased frequency of inguinal hernias in the epinephrine-exposed group (Heinonen et al et al., 1977). However, it is unlikely that 118 118 Anaesthetic agents and surgery during pregnancy epinephrine is a teratogen. Epinephrine is also used as a test agent to detect intravascular injection of local anesthetics.
Some local anesthetics (e.g., lidocaine), especially those used in combination with epinephrine, have been a.s.sociated with fetal heart rate bradycardia when utilized for paracervical block anesthesia during labor. It has been suggested that bradycardia is secondary to vasoconstriction of uterine artery caused by the anesthetic agent (Fishburne et al. et al. , 1979). Thus paracervical blocking techniques are not recommended in the presence of fetal heart rate abnormalities or compromised uterine blood flow (Carlsson , 1979). Thus paracervical blocking techniques are not recommended in the presence of fetal heart rate abnormalities or compromised uterine blood flow (Carlsson et al et al., 1987).
GENERAL ANESTHETICS.
Regional anesthetic techniques are preferred for pregnant women undergoing obstetrical procedures, general anesthesia often used for non.o.bstetrical or emergency procedures in pregnant women. The fetus will be exposed to a variety of agents that include narcotics, paralyzing agents, and inhalational anesthetic agents.
Thiopental and ketamine Thiopental and ketamine are narcotic anesthetics, and are given intravenously for rapid induction of anesthesia prior to the intubation and initiation of inhalational anesthetic agents. Thiopental is the most often used agent for this purpose. The frequency of congenital malformations was not increased in human or animal studies (Heinonen et al et al., 1977; Friedman, 1988). Ketamine is rarely used in obstetrics, except for rapid anesthesia in emergency operative v.a.g.i.n.al deliveries. Ketamine presents two problems: (1) clinically significant increase in blood pressure; and (2) significant maternal hallucinations.
Ketamine was not teratogenic in one animal study (Friedman, 1988).
NEUROMUSCULAR BLOCKING AGENTS.
The most commonly used agent for inducing paralysis prior to intubation and the initiation of actual surgical procedures is probably succinylcholine. Perhaps 20 percent of patients have lowered cholinesterase activity, and pregnancy reduces cholinesterase activity in general. Therefore, pregnant patients probably require a smaller dose of succinylcholine than nongravid women. Newborns may be exposed to enough drug to experience neuromuscular blockade that requires supportive therapy. Other common agents used for neuromuscular blockade are vecuronium bromide, pancuronium bromide, and atracurium besylate (Box 6.2). Unlike succinylcholine, which is a depolarizing agent, these three neuromuscular blocking agents are nonpolarizing in action.
Box 6.2 Neuromuscular blocking agents Depolarizing agents Succinylcholine (Anectine) Nondepolarizing agents Atracurium besylate (Tracrium) Pancuronium bromide (Pavulen) Vecuronium bromide (Norcuron) Inhgaled anesthesia agents 119.
As mentioned above, this cla.s.s of neuromuscular agents may require a dose increase because of a reduced half-life and increased renal clearance (Little, 1999). No reports are published regarding these neuromuscular blocking agents. However, according to its manufacturer, atracurium is potentially teratogenic in animals.
INHALED ANESTHESIA AGENTS.
Commonly utilized inhalation agents for general anesthesia include nitrous oxide, halothane, methoxyflurane, enflurane, and isoflurane. Neither ether nor cyclopropane is commonly used in present-day anesthetic techniques, and there have been no adequate human studies regarding potential teratogenicity of either of these agents (Friedman, 1988).
Halothane and other halogenated agents Halogenated agents are often used to supplement the standard nitrous oxide, thiopental and muscle relaxant regimens for balanced general anesthesia. Use of halogenated agents decreases maternal awareness and recall, allows for a higher percentage of inspired oxygen, and results in higher fetal oxygen concentrations (Shnider and Levinson, 1979).
The prototype halogenated anesthetic agent was not found to be a.s.sociated with an increased risk of congenital malformations in children whose mothers received this agent during the first 4 months (Heinonen et al et al., 1977), but there were only 26 infants exposed. Increased fetal loss, growth r.e.t.a.r.dation, malformations, and behavioral abnormalities have been reported with the use of halothane in animal studies (Friedman, 1988). No epidemiologic studies of congenital anomalies with the use of the other halogenated agents (enflurane, methoxyflurane, isoflurane) have been published. These agents were reported to cause a variety of malformations in animal studies at doses many times those used in humans (Friedman, 1988).
Placental transfer of enflurane and halothane in women who were delivered via Caesarean section had no apparent adverse effects on Apgar scores, newborn acidbase status, and early neonatal neurobehavioral scores. Significant levels of both of these agents were achieved in the fetus at about 5060 percent of maternal concentrations (Abboud et al et al., 1985).
Halogenated agents have also been reported to be a.s.sociated with an increase in blood loss in the mother at the time of Caesarean section in some studies (Gilstrap et al et al., 1987), but others have found no a.s.sociation between blood loss and use of halogenated agents, especially when used in low doses for Caesarean section (Abboud et al et al., 1985; Lamont et al et al., 1988; Warren et al et al., 1983).
Increased blood loss from uterine relaxation may occur, especially in prolonged high-dose use. Otherwise, it seems apparent that halogenated agents are safe for both mother and fetus, although the data are not conclusive.
Nitrous oxide Nitrous oxide is the most commonly used inhalation anesthetic agent in obstetrics, and is usually part of a balanced general anesthetic regimen that includes: a fast-acting 120 120 Anaesthetic agents and surgery during pregnancy barbiturate (e.g., thiopental), a muscle relaxant (e.g., succinylcholine), and a halogenated agent (e.g., isoflurane). The frequency of congenital anomalies was not increased among more than 500 infants exposed to nitrous oxide during the first trimester (Heinonen et al et al., 1977; Crawford and Lewis, 1986). As with many other agents, nitrous oxide has been reported to be a.s.sociated with increased fetal resorption, growth r.e.t.a.r.dation, and congenital anomalies in animal studies (Friedman, 1988; Mazze et al et al., 1984).
Some anesthetists have used high concentrations (e.g., 70 percent nitrous oxide, 30 percent oxygen). Lower nitrous oxide concentrations (50 percent) have been used with higher oxygen concentrations (50 percent), responding primarily to concerns that higher nitrous oxide concentrations may be a.s.sociated with neurobehavioral alterations.
Altered neonatal neurobehavioral effects are a.s.sociated with nitrous oxide and halothane and have been demonstrated in animal studies (Koeter and Rodier, 1986; Mullenix et al et al., 1986). Current recommendations are to use lower concentrations of nitrous oxide, higher concentrations of oxygen, and to add a halogenated agent to the regimen.
SYSTEMIC a.n.a.lGESICS.
Systemic a.n.a.lgesics (meperidine, morphine, pentazocine, butorphanel, alphaprodine) are used for a.n.a.lgesia for women in labor and are discussed in the chapter on a.n.a.lgesics (Chapter 8). Three very potent synthetic opioid a.n.a.lgesics (fentanyl, sufentanil, and alfetanil) (Box 6.3) are often used as: (1) premedication prior to surgery; (2) an adjunct for induction of anesthesia; and (3) an adjunct in maintaining general anesthesia. Fentanyl is also used in combination with a neuroleptic agent (droperidol) for the same indications. None of these narcotic agents has been shown to be teratogenic in a variety of animal studies. First trimester exposure to meperidine was not a.s.sociated with an increased frequency of congenital anomalies among 268 infants (Heinonen et al et al., 1977). Similarly, morphine was not teratogenic in humans (Table 6.3). Intravenous fentanyl was not a.s.sociated with low Apgar scores or neonatal respiratory depression compared to controls (Rayburn et al et al., 1989).
Three synthetic narcotic a.n.a.lgesics (fentanyl, sufentanil, and alfetanil) have been used as an adjunct to epidural a.n.a.lgesia during labor (Ross and Hughes, 1987). However, neonatal respiratory depression is a risk with use of these agents during labor.
Box 6.3 Agents utilized for or as adjuncts for general anesthesia Inhalational agents Inhalational agents Narcotic Enflurane (Ethrane) Alfentanil (Alfenta) Halothane (Fluothane) Fentanyl (Sublimaze) Isoflurane (Forane) Fentanyl + Droperidol (Innovar) Methoxyflurane (Penthrane) Sufentanil (Sufenta) Other Ketamine (Ketalar) Thiopental Special considerations 121.
Table 6.3 Summary of cardiovascular anaesthetics drugs: Teratogen Information System (TERIS) and Food and Drug Administration (FDA) risk estimates Drug Summary of cardiovascular anaesthetics drugs: Teratogen Information System (TERIS) and Food and Drug Administration (FDA) risk estimates Drug Risk Risk rating Atracurium Undetermined Cm Benzocaine Unlikely NA.
Bupivacaine Undetermined NA.
Cyclopropane Undetermined NA.
Diazepam Minimal D.
Droperidol Undetermined Cm Enflurane Undetermined NA.
Epinephrine Unlikely C.
Ether Undetermined NA.
Fentanyl Undetermined C *
m Halothane Undetermined NA.
Isoflurane Undetermined NA.
Ketamine Undetermined B.
Lidocaine Local administration: none Bm Intravenous administration: undetermined Meperidine Unlikely B*
Methoxyflurane Undetermined NA.
Morphine Congenital anomalies: unlikely C *
m Neonatal neurobehavioral effects: moderate Nitrous oxide Occupational exposure: unlikely NA Anesthesia: unlikely Pancuronium Undetermined Cm Prilocaine Undetermined NA.
Procaine None NA.
Succinylcholine Unlikely Cm Tetracaine Undetermined NA.
Thiopental Unlikely NA.
Vecuronium Undetermined NA.
NA, not available.
Compiled from: Friedman et al., Obstet Gynecol 1990; 75 75: 594; Briggs et al., 2005; Friedman and Polifka, 2006.
SPECIAL CONSIDERATIONS.
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