Opiates, sedatives, and tranquilizers are contraindicated in asthmatics because they cause alveolar ventilatory depression, and are a.s.sociated with respiratory arrest immediately after use (Table 5.4). Beta-adrenergic blockers and parasympathetic agents should also be avoided in asthmatics because they can cause bronchospasm.

Additionally, if prostaglandins are needed for labor induction or termination of pregnancy, prostaglandin E (PGE ), a bronchodilator, should be administered, rather than 2 2.prostaglandin F (PGF ), because it has potent bronchoconstricting effects and may 2a 2a Key references 113.

precipitate status asthmaticus (Fishburne et al et al., 1972a, 1972b; Hyman et al et al., 1978; Smith, 1973).

Chronic asthma Chronic asthma patients need additional steroid therapy for coverage during the stress of labor if they have received oral steroid therapy for more than 2 weeks within the previous year to prevent adrenal crisis. Hydrocortisone, 100 mg IM or IV every 68 h for 24 h, is usually given. Corticosteroids should be given in cases of severe or mild asthma with wheezing that is unresponsive to bronchodilators. Initially, prednisone, 3060 mg daily is given to prevent status asthmaticus. Beclomethasone dipropionate is effective and safe when prolonged steroid use is necessary.

Beta-agonist by inhalation every 34 h as needed is used for outpatient management of chronic asthma, along with inhalation steroids such as beclomethasone (Cunningham, 1994).

Cromolyn sodium can be given chronically by inhalation, and is fairly effective in improving the symptoms of an asthmatic. An added benefit with cromolyn use is a decreased requirement for other antiasthma agents. Cromolyn therapy is best begun during remissions because it requires several days to reach an effective dosing regimen.

Medications that cause bronchospasm or depress alveolar ventilation should be avoided in the pregnant woman with asthma (Table 5.4).

Key references ACOG (American College of Obstetricians and Gynecologists). Pulmonary Disease in Pregnancy. Technical Bulletin No. 224, American College of Obstetricians and Gynecologists, Washington, DC, June 1996.

Briggs GG, Freeman RK, Yaffe SJ. Drugs in Pregnancy and Lactation. A Reference Guide to Fetal and Neonatal Risk, 6th edn. Philadelphia: Lippincott Williams & Wilkins, 2005: 8734.

Dombrowski, M.P. Pharmacologic therapy of asthma during pregnancy. Obstet Gynecol Clin North Am 1997; 24 24: 55974.

Jana N, Vasishta K, Saha SC, Khunnu B. Effect of bronchial asthma on the course of pregnancy, labour and perinatal outcome. J Obstet Gynaecol 1995; 21 21: 227.

Kallen B, Rydhstroem H, Aberg A. Asthma during pregnancy a population-based study. Eur J Epidemiol 2000; 16 16: 16771.

Little BB. Pharmac.o.kinetics during pregnancy. Evidence-based maternal dose formulation.

Obstet Gynecol 1999; 93 93: 85868.

Schatz M. The efficacy and safety of asthma medications during pregnancy. Semin Perinatol 2001; 25 25: 14552.

Stenius-Aarniala B, Hedman J, Teramo KA. Acute asthma during pregnancy. Thorax 1996; 51 51: 411.

Stenius-Aarniala B, Riikonen S, Teramo K. Slow-release theophylline in pregnant asthmatics.

Chest 1995; 107 107: 642.

Weinberger M, Hendeles L. Theophylline in asthma. N Engl J Med 1996; 334 334: 1380.

Wendel PJ, Ramin SM, Barnett-Hamm C, Rowe TF, Cunningham FG. Asthma treatment in pregnancy. A randomized controlled study. Am J Obstet Gynecol 1996; 175 175: 150.

Further references are available on the book's website at http://www.drugsandpregnancy.com 6.Anesthetic agents and surgery during pregnancy Anesthetic agents 117.

Inhaled anesthesia agents 119.

Local anesthetics 117.

Systemic a.n.a.lgesics 120.

General anesthetics 118.

Special considerations 121.

Neuromuscular blocking agents 118.

Key references 125.

Surgery during pregnancy is necessary among approximately 12 percent of gravidas in the USA (Brodsky, 1983; Friedman, 1988). Many surgeons are reluctant to perform operative procedures on women known to be pregnant, although emergency procedures are sometimes necessary. In addition, elective or indicated procedures may be carried out on women with an unrecognized pregnancy. Obstetrical surgery (i.e., Caesarean section) is increasingly common with a steady rise in the Caesarean section rate from 45 percent in the 1960s to rates exceeding 20 percent in contemporary practice (Gilstrap et al et al., 1984; Notzon et al et al., 1987).

General principles that the clinician should be aware of when surgery is antic.i.p.ated in a pregnant woman are based on physiologic differences between the pregnant and nonpregnant state (Box 6.1). Most importantly, two patients are involved, the mother and her fetus. Virtually all anesthetic agents and 98 percent of medications cross the placenta, exposing the fetus to medically significant levels. In addition, mild changes in maternal cardiopulmonary status (i.e., changes in blood pressure or oxygen saturation) may have physiologically important sequelae for the fetus, but are of little consequence Box 6.1 General principles regarding surgery and anesthesia Box 6.1 General principles regarding surgery and anesthesia during pregnancy during pregnancy Two patients: Mother and embrofetus a.s.sume that all anesthetics and 98 percent of medications cross the placenta, resulting in fetal levels Minor maternal cardiopulmonary status changes may have profound effects on the fetus Numerous maternal physiological changes occur during pregnancy (Table 6.1) Aspiration pneumonitis risk is increased during pregnancy Laboratory and radiologic procedures should be performed as indicated Indicated surgery during pregnancy showed be performed statim because delays increase risks of morbidity and mortality Anesthetic agents and surgery during pregnancy 115.

to the mother. Even a minimal degree of hypotension and hypoxia is to be avoided because this may result in placental hypoperfusion and fetal hypoxemia. Pregnant women being prepared for surgery should be placed on their left side, adequately hydrated, and preoxygenated prior to induction of anesthesia.

Pharmac.o.kinetics of anesthetic agents have been reported for only pancuronium, and its disposition was a pregnancy-a.s.sociated decreased half-life, and this was probably due to significantly increased clearance (Little, 1999).

Table 6.1 Physiologic changes in pregnancy Physiologic changes in pregnancy System Cardiovascular Cardiac output Increase Blood volume Increase Heart rate Increase Blood pressure Initial decreasea Peripheral resistance Decrease Hematocrit Decrease Hematologic Leukocytes Increase Fibrinogen (I) Increase Factors VIIX Increase Factors II Slow increase Factors XI, XIII Decrease Platelets Unchanged Prothrombin time/ partial thromboplastin time Slow decrease Respiratory Tidal volume Increase Vital capacity Unchanged Functional residual capacity Decrease Compliance Unchanged Minute ventilation Increase pCO Decrease 2.HCO.

Decrease 3.Renal Serum creatinine Decrease Serum blood urea nitrogen Decrease Creatinine clearance Increase Gastrointestinal Gastric emptying Decrease Cardiac valve competency Decrease Regurgitation Increase aReturns to prepregnancy levels by term.

From Little, 1999; Gilstrap and Hankins, 1988.

116.

Anaesthetic agents and surgery during pregnancy Several maternal physiologic changes occur during pregnancy (Table 6.1), and the most marked is expansion of the maternal blood volume by up to 50 percent. Increased blood volume is caused by a plasma volume increase of approximately 1000 cc and a 300500 cc increase in red cells. This usually results in lower hematocrit compared to the nonpregnant woman, and is commonly known as physiologic anemia of pregnancy.

Increased renal blood flow is a result of the increase in blood volume. Accordingly, the glomerular filtration rate increases (as measured by the endogenous creatinine clearance) because of increased blood volume. Serum creatinine and blood urea nitrogen decrease because of dilution by increased plasma volume. Other changes in the renal system include dilatation of the ureters and a relative stasis of urine, resulting in a 'relative'

hydronephrosis. The relative hydronephrosis is frequently more p.r.o.nounced on the right than on the left side.

Other cardiopulmonary changes that occur during pregnancy include a slight increase in heart rate, and decreased systolic and diastolic blood pressures in the second trimester.

Blood pressure gradually returns to prepregnancy levels by the third trimester. Most women have a systolic flow murmur by midpregnancy. Respiratory rate increases slightly during pregnancy with a decrease in physiologic 'dead s.p.a.ce' as pregnancy progresses. Tidal volume is increased during pregnancy, but minute ventilation and compliance do not change during pregnancy. Blood pCO and HCO decrease during preg-2 3.nancy, while pH is slightly increased during pregnancy. Hence, upper normal range pCO for nonpregnant women probably indicates CO retention.

2.2.Gastrointestinal system changes with pregnancy affect pregnant women that require anesthesia and/or surgery. The risk for aspiration pneumonitis in surgery on the gravid patient is increased because of pregnancy-a.s.sociated decreases in intestinal motility and gastric emptying. Hepatic function is also altered during pregnancy. Maternal alkaline phosphatase levels are increased during gestation.

Liver cytochrome P-450 (CYP) 3A4 and CYP2D6 activities increase during pregnancy. Importantly, the enzyme responsible for metabolism of 50 percent of pharmacologic agents (CYP1A2) is downregulated. This has implications for anesthesia dose management of the pregnant patient; lower doses than in the nongravid patient may achieve the desired anesthetic effect. CYP2C19 activity is upregulated in pregnant compared to nonpregnant women, but even during pregnancy its activity is not higher than normal adult male levels. Extrahepatic enzymes (e.g., cholinesterase) that also metabolize some anesthetics have diminished activity during pregnancy.

Liver fibrinogen production is also increased during pregnancy. Serum levels as high as 400 mg percent are not unusual during the third trimester and cause increased red cell sedimentation rate in pregnant women. Hematocrit is decreased during pregnancy accompanied by a relative leukocytosis (white blood cell count greater than or equal to 10 00012 000 or even higher during labor). Several hematologic measures are unchanged during pregnancy: for example, the relative percent of immature forms (i.e., 'bands'), lymphocytes, eosinophils, and platelet count.

Whole blood clotting time, prothrombin time, and partial thromboplastin time remain in normal ranges during pregnancy.

Surgery should be performed without delay when it is indicated for life-threatening maternal conditions. Indicated laboratory tests and radiologic procedures should be performed without hesitation to properly guide life-saving surgical procedures.

Local anesthetics 117.

ANESTHETIC AGENTS.

Secondary effects of anesthetic agents (hypotension, hypoxia) are important to avoid in the gravid patient as these may cause adverse fetal effects. Anesthetic adjuncts, or other 'nonanesthetic' drugs and medications during the pre-, intra-, and post-operative periods may also adversely affect the fetus.

LOCAL ANESTHETICS.

Local anesthetics may be injected in subdural or epidural s.p.a.ces for regional anesthesia (Table 6.2). Topical application results in negligible fetal exposure and minimal risk.

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 (Morishima 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.