Ductus closure has been demonstrated in animal models, but not reported in humans.

ETODOLAC.

Etodolac is a c.o.x-2 selective a.n.a.lgesic. No studies of congenital anomalies in offspring exposed to etodolac during the first trimester have been published. Premature closure of the ductus arteriosus is a theoretical risk because of the pharmacologic action of etodolac. Etodolac was found to be safer for the gastrointestinal tract (i.e., fewer bleeding ulcers than naproxen) with chronic therapy (Weideman et al et al., 2004). The frequency of congenital anomalies was increased among rats or rabbits exposed to etodolac during embryogenesis (Ninomiya et al et al., 1990a, 1990b).

Narcotic a.n.a.lgesics Some of the more commonly used a.n.a.lgesics are listed in Box 8.2. All of the opioid narcotic a.n.a.lgesics cross the placenta and have the potential to cause dependence and withdrawal symptoms in the fetus and newborn if regularly used or abused (see Chapter 16 regarding substance abuse). Many of these agents are commonly used for the relief of Box 8.2 Narcotic a.n.a.lgesics Box 8.2 Narcotic a.n.a.lgesics Alphaprodine Morphine Butorphanol Nalbuphine Codeine Oxycodone Fentanyl Oxymorphone Hydrocodone Pentazocine Hydromorphone Propoxyphene Meperidine Sufentanil 156.

a.n.a.lgesics during pregnancy pain during labor and as such are a.s.sociated with few, if any, adverse fetal effects, with the possible exception of respiratory depression if used in sufficiently large doses close to delivery.

MEPERIDINE.

Meperidine is one of the most commonly used a.n.a.lgesics during labor. Within 7 min of maternal injection, fetal levels are about equal to maternal levels (Fishburne, 1982; Spielman, 1987). The half-life in the newborn may be up to 23 h (Spielman, 1987).

Meperidine is metabolized predominantly in the liver, and its major metabolite, normeperidine, is more potent and potentially more toxic than the parent compound itself.

The frequency of congenital anomalies was not increased among more than 300 infants born to women who took this a.n.a.lgesic in the first trimester (Heinonen et al et al., 1977; Jick et al et al., 1981). Neonates may manifest respiratory depression and behavioral changes because of the long half-life of this drug in the fetus and newborn (Belsey et al et al., 1981; Busacca et al et al., 1982; Koch and Wendel, 1968; Morrison et al et al., 1973; Schnider and Moya, 1964). The neonatal behavioral changes are, however, transient as shown in a 5-to 10-year follow-up of 70 children born to mothers who received meperidine during labor. There were no significant persisting physical or psychological effects as a result of this medication (Buck, 1975). The frequency of central nervous system anomalies was increased in the offspring of hamsters who received meperidine in doses several times that used in humans (Geber and Schramm, 1975).

Meperidine is apparently a safe drug for use during pregnancy when taken within the therapeutic dose range, especially during labor. The dose needs extra consideration because of the long half-life of this drug in the neonate.

MORPHINE.

Morphine is no longer commonly used as an a.n.a.lgesic during labor because neonatal respiratory depression occurs with a significantly greater frequency than with meperidine (Spielman, 1987). Nonetheless, pregnant women may be exposed to this narcotic a.n.a.lgesic for other indications (e.g., postoperative pain). The frequency of birth defects was no greater than expected among the offspring of 70 women who received this drug during the first trimester of pregnancy (Heinonen et al et al., 1977). Two animal studies found that morphine exposure during embryogenesis did not increase the frequency of congenital anomalies (Fujinaga and Mazze, 1988; Yamamoto et al et al., 1972). Three other experimental animal studies did find an increase in the central nervous system and other abnormalities in the offspring of animals treated with morphine in doses several times larger than those used in humans (Geber, 1977; Geber and Schramm, 1975; Harpel and Gautierie, 1968).

Newborns of addicted mothers may experience withdrawal symptoms, and this is discussed in more detail in the chapter on substance abuse (Chapter 16).

PENTAZOCINE.

Pentazocine is a narcotic a.n.a.lgesic used for the relief of moderate to severe pain and is a.s.sociated with a risk of respiratory depression similar to other narcotics. It crosses the placenta readily, but evidently not to the same extent as meperidine (Spielman, 1987).

Nonsteroidal antiinflammatory agents 157.

The frequency of congenital anomalies was not increased in two studies encompa.s.sing 63 infants born to mothers who utilized pentazocine in a.s.sociation with tripelennamine, i.e., Ts and blues (see Chapter 16) (Chasnoff et al et al., 1983; Senay, 1985). In another study, the frequency of congenital anomalies was increased but concomitant heavy alcohol use in the study cohort was probably the proximate cause of the birth defects observed (Little et al et al., 1990). The authors concluded that it was very unlikely that the anomalies found were a.s.sociated with the abuse of pentazocine.

An increased frequency of low birth weight infants was a.s.sociated with the use of pentazocine and tripelennamine during pregnancy (Chasnoff et al et al., 1983; Dunn and Reynolds, 1982; Little et al et al., 1990; von Almen and Miller, 1986). No epidemiologic studies are published regarding the possible a.s.sociation of congenital anomalies with the therapeutic use of pentazocine.

There was an increased frequency of central nervous system defects in the offspring of hamsters which had received large doses of pentazocine, but not with smaller doses (Geber and Schramm, 1975).

As with all narcotics, fetal addiction and severe neonatal withdrawal symptoms occur with habitual maternal use of pentazocine (Goetz and Bain, 1974; Kopelman, 1975; Little et al et al., 1990; Scanlon, 1974).

BUTORPHANOL.

Butorphanol is a parenterally administered labor a.n.a.lgesic with agonist and antagonist actions (Spielman, 1987). The main advantage of butorphanel is that it has the efficacy of other narcotic a.n.a.lgesics, but respiratory depressive effects are less of a risk than with other narcotics. The butorphanol metabolite has no a.n.a.lgesic or toxic effect, unlike meperidine, which is an advantage in the management of maternal dose and untoward neonatal effects (Spielman, 1987), because this agent readily crosses the placenta (Pittman et al et al., 1980). Importantly, it may cause fetal and neonatal cardiorespiratory depression at high and frequent dose regimens. Chronic use/abuse of this agent during pregnancy may lead to fetal dependence and severe neonatal withdrawal symptoms.

No studies regarding the use of this agent during pregnancy and the frequency of congenital anomalies have been published. However, butorphanel is not considered to increase the risk of birth defects substantially (Friedman and Polifka, 2006). The frequency of congenital anomalies among offspring exposed to butorphanol during embryogenesis was not increased above that observed in offspring of sham controls (Takahashi et al et al., 1982).

Butorphanol is compatible with breastfeeding (American Academy of Pediatrics, 1994).

HYDROCODONE.

Hydrocodone is a synthetic narcotic used to treat moderate pain but it is not often used during labor and delivery. It is also used as a cough suppressant. The frequency of congenital anomalies (7.2 percent) was slightly increased above that expected in the general population (5 percent) in an unpublished study of 332 women who received prescriptions for this drug in the first trimester (Rosa, personal communication, cited in Briggs et al. et al. , 2005). No pattern of anomalies was observed in a clinical case series of 40 infants whose mothers used hydrocodone during the first trimester (Schick , 2005). No pattern of anomalies was observed in a clinical case series of 40 infants whose mothers used hydrocodone during the first trimester (Schick et al et al., 1996). An increased frequency of malformations was found in the offspring of animals that received extremely large doses of this agent (Geber and Schramm, 1975).

158.

a.n.a.lgesics during pregnancy OXYMORPHONE.

Oxymorphone is another narcotic a.n.a.lgesic, and no published reports are available regarding potential teratogenic effects in humans. Several early studies regarding the use of this a.n.a.lgesic during labor a.s.sociate it with newborn respiratory depression (Sentnor et al et al., 1962; Simeckova et al et al., 1960).

An increased frequency of malformations was observed in offspring of animals given oxymorphone during embryogenesis, but a dose 5000 times that normally used in humans was used (Geber and Schramm, 1975).

OXYCODONE.

Among 78 infants exposed to oxycodone during the first trimester, the frequency of birth defects was not increased above population background levels (3.55 percent) (Schick et al et al., 1996). In an unpublished study, the frequency of birth defects among 281 infants born to women who were prescribed oxycodone during the first trimester was not increased (Rosa, 1993). There are no published animal reproduction studies.

Pharmacologically, this a.n.a.lgesic is expected to result in neonatal respiratory depression and possibly withdrawal symptoms. Although there is a paucity of information regarding the last three drugs (hydrocodone, oxymorphone, and oxycodone), they are listed as FDA category B drugs by their manufacturers.

ALPHAPRODINE.

Although this narcotic a.n.a.lgesic has been available since the 1940s (Hapke and Barnes, 1949), there are no available large human reproduction studies. Alphaprodine crosses the placenta readily and may result in newborn respiratory depression. This agent is no longer commonly used during pregnancy because of the potential for causing a sinusoidal heart rate pattern in the fetus (Gray et al et al., 1978).

FENTANYL.

Fentanyl is a synthetic narcotic that is 1000 times more potent than meperidine (Spielman, 1987). No studies have been published on the use of fentanyl during the first trimester. It may, however, cause respiratory depression with chronic maternal use in the third trimester (Regan et al et al., 2000). No birth defects were found among rats given high doses of this drug throughout gestation (Fujinaga et al et al., 1986).

Alfentanil and sufentanil are discussed in Chapter 6.

PROPOXYPHENE.

Propoxyphene is a commonly used a.n.a.lgesic agent similar in structure to methadone. It has neither an antipyretic nor antiinflammatory action. In epidemiological investigations, the frequency of congenital anomalies was not increased among the offspring of almost 800 women who used this agent during early pregnancy (Heinonen et al et al., 1977; Jick et al et al., 1981). A few case reports of malformations in the offspring of mothers who utilized propoxyphene during pregnancy have been published (Golden et al et al., 1982; Williams et al et al., 1983), but no causal links can be established. Propoxyphene is not teratogenic in rabbit, hamster, rat, or mouse animal models at doses 40-fold greater than the usual human dose (b.u.t.tar and Moffatt, 1983; Emmerson et al et al., 1971).

Nonsteroidal antiinflammatory agents 159.

A neonatal withdrawal syndrome (irritability, hyperactivity, tremors, high-pitched cry) was reported among newborns of mothers who used propoxyphene chronically during late pregnancy (Ente and Mehra, 1978; Klein et al et al., 1975; Quillian and Dunn, 1976; Tyson, 1974). Propoxyphene is opined to be safe for breastfeeding mothers (American Academy of Pediatrics, 1994).

NALBUPHINE.

Nalbuphine is an opiate a.n.a.lgesic given parenterally for moderate to severe pain, or as an adjunct to balanced general anesthesia or regional techniques. This narcotic crosses the placenta readily. Nalbuphine, as other narcotics, has the potential to result in neonatal respiratory depression, fetal and neonatal addiction, fetal cardiac function alterations, and withdrawal symptoms in the newborn. For example, this agent was a.s.sociated with a sinusoidal fetal heart rate pattern, similar to that produced by alphaprodine (Feinstein et al et al., 1986).

No studies have been published regarding use of this agent during pregnancy during the first trimester. However, according to the manufacturer, this agent was not teratogenic in animal studies.

Narcotic antagonists These are agents used primarily for the treatment of central nervous system and cardiorespiratory depression secondary to narcotic agonists.

NALOXONE.

Naloxone (Narcan), a synthetic congener of oxymorphone, is the most commonly used antagonist agent for reversal of narcotic depression in the newborn. No studies have been published regarding congenital anomalies among the offspring of women who took this drug in the first trimester.

In experimental animal studies (hamsters, mice), the frequency of congenital anomalies was not increased among offspring exposed to naloxone at many times the usual human dose (Geber and Schramm, 1975; Jurand, 1985). It is well known that naloxone may precipitate withdrawal symptoms in newborns whose mothers are addicted to narcotics, and who used very high doses of narcotics near the time of delivery.

NALTREXONE.

Another narcotic antagonist, naltrexone (Trexan), is also a congener of oxymorphone.

No studies have been published on congenital anomalies after exposure to naltrexone during embryogenesis. Three case series comprising reportedly nonoverlapping patients contained 31 infants whose mothers used naltrexone during the first trimester, and there were no congenital anomalies present (Hulse and O'Neil, 2002; Hulse et al et al., 2001, 2004). Notably, these gravidas were given naltrexone as part of a treatment regimen for heroin addiction. According to its manufacturer, this agent was shown to be embryocidal in animal studies. Independent investigators have reported no increased frequency of congenital anomalies among rats or rabbits exposed during embryogenesis.

160.

a.n.a.lgesics during pregnancy OTHER a.n.a.lGESICS.

Butalbital Butalbital is a short-acting barbiturate that is contained in a variety (over 40) of available prescription a.n.a.lgesic compounds. Butalbital is usually combined with aspirin or acetaminophen (with or without caffeine). The most common indication for butalbital-containing a.n.a.lgesic compounds is tension headaches. All barbiturates cross the placenta, as do acetaminophen and aspirin. Barbiturate use in the first trimester was not a.s.sociated with an increase in the frequency of congenital anomalies in exposed offspring. However, barbiturates have been a.s.sociated with fetal dependence and newborn withdrawal symptoms when used chronically by the mother in the third trimester.

Medical compounds comprised of isometheptene, dichloralphen.a.z.ine and acetaminophen (Midrin, Amidrin, Migratine) are used to treat vascular headaches or migraines.

Isometheptene, a sympathomimetic drug, causes vasoconstriction. Dichloralphenazone is a mild sedative. This combination is commonly used during pregnancy, but no studies of the risk of congenital anomalies are available for two of the components (isometheptene, dichloralphen.a.z.ine).

Sumatriptan and other triptans Sumatriptan (Imitrex) is a selective 5-hydroxytryptamine receptor agonist. It is used primarily as acute therapy for migraine headaches. Among 658 infants born to women who used sumatriptan during the first trimester, the frequency of congenital anomalies was no greater than expected (Kallen and Lynger, 2001). According to its manufacturer, it has been shown to cause malformations in rabbits but was not teratogenic in rats. Using the ex vivo ex vivo isolated perfused cotyledon technique, sumatriptan crossed the placenta by pa.s.sive transport in the isolated perfused cotyledon technique, sumatriptan crossed the placenta by pa.s.sive transport in the ex vivo ex vivo isolated perfused cotyledon technique (Schenker isolated perfused cotyledon technique (Schenker et al et al., 1995). This drug is listed as an FDA category C agent, but seems to be safe for use during pregnancy (Table 8.2). Other triptans include nartriptan, almotriptan, rizatriptan, zolmitriptan. None have been adequately studied during pregnancy.

SPECIAL CONSIDERATIONS.

Labor a.n.a.lgesics MEPERIDINE.

Meperidine provides effective pain relief for 24 h in most patients who need systemic labor a.n.a.lgesics. The usual dose is 2550 mg IV or 5075 mg IM. Promethazine, in a dose of 25 mg, is also usually given as an adjunct to prevent nausea (Table 8.3).

BUTORPHENOL.

Butorphenol is also a very effective narcotic for systemic a.n.a.lgesia and is usually given in a dose of 12 mg either IV or IM. This agent provides pain relief for up to 4 h.

Special considerations 161.

Table 8.2 Comparison of Teratogen Information System (TERIS) risk and Food and Drug Administration (FDA) pregnancy risk ratings Comparison of Teratogen Information System (TERIS) risk and Food and Drug Administration (FDA) pregnancy risk ratings Drug Risk Risk rating Acetaminophen None B.

Butalbital Unlikely C*

Butorphanol Undetermined C *

m Fenoprofen Undetermined B*

Fentanyl Undetermined C *

m Hydrocodone Unlikely C*

Hydromorphone Unlikely B*

Ibuprofen Minimal B *

m Indomethacin None to minimal B*

Isometheptene Undetermined C.

Meclofenamate Undetermined B*

Meperidine Unlikely B*

Methadone Unlikely B*

Morphine Congenital anomalies: unlikely neonatal neurobehavioral C *

m Effects: moderate Nalbuphine Undetermined B *

m Naloxone Undetermined Bm Naltrexone Undetermined Cm Naproxen Undetermined B *

m Oxycodone Undetermined B *

m Oxymorphone Undetermined B*

Pentazocine Unlikely C*

Phenacetin None B.

Phenylbutazone Undetermined C *

m Promethazine None C.

Propoxyphene None C*

Propranolol Undetermined C *

m Sulindac Undetermined B*

Sumatriptan Unlikely Cm Compiled from: Friedman et al., 1990; Briggs et al., 2005; Friedman and Polifka, 2006.

a.n.a.lgesia following minor procedures Several oral narcotic agents (hydrocodone, oxycodone) provide satisfactory relief for moderate pain a.s.sociated with minor surgical procedures, such as dental procedures. Narcotic agents should not be used over a protracted period of time (more than 7 days) late in pregnancy because of the potential for neonatal dependence or withdrawal symptoms.

Headache Headaches are common during pregnancy and may increase in frequency during gestation. In all headache syndromes, potential identifiable causes of headaches should be ruled out before a long-term treatment plan is implemented. Headache etiology in most 162 162 a.n.a.lgesics during pregnancy patients is unknown. Headaches are divided into two major categories: (1) tension and (2) vascular (migraine). For mild to moderate headaches, aspirin, acetaminophen, ibuprofen, or naproxen usually provide satisfactory relief. Acetaminophen is the preferred a.n.a.lgesic for use during pregnancy. Aspirin should be avoided during pregnancy for hematologic reasons, and especially when headaches occur close to term. Aspirin increases the potential for increased bleeding from salicylcate use. More generally, NSAIDS should not be used after 34 weeks gestational age because of the theoretical potential for premature closure of the ductus arteriosus and other potential adverse effects. If other agents have failed, ibuprofen appears to pose the least risk for increased bleeding and premature ductus closure.

Migraine (vascular) headaches are difficult to treat during pregnancy, and they seem to increase in frequency during gestation. The vasoconstrictive agent, ergotamine, is one of the agents used to treat migraine headaches in the nonpregnant patient; however, it is not recommended for use during pregnancy because it has (1) vasoconstrictive and (2) oxytocin-like actions. Propranolol at a dose of 40 mg or higher per day (several divided doses) has been effective for the treatment of some migraines in the pregnant patient, and poses a negligible risk to the unborn child.

Amitriptyline, a tricyclic antidepressant, has been used to treat migraine headaches in pregnant women. However, this agent should be used as a third line of medical treatment for migraine headaches among pregnant women with vascular headaches who have not responded to a.n.a.lgesics or propranolol.

The combination of isomethertene, dichloralphenazone, and acetaminophen is also used for treatment of migraine headaches during pregnancy. However, the effects of isomethertene and dichloralphenazone are unknown. Importantly, this combination of drugs should be avoided in women with hypertension. The usual dose is two capsules orally at the beginning of an attack and then one capsule every hour; up to five capsules in any one 12-h period (see manufacturer's prescribing recommendations).

Sumatriptan (Imitrex) has been studied sufficiently to state that the risk of congenital anomalies following first trimester exposure is not greater than that in the general population (Kallen and Lygner, 2001).

As emphasized earlier, narcotic a.n.a.lgesics should not be utilized on a chronic basis for headaches because of the potential for addiction in the mother and withdrawal symptoms in the fetus. However, narcotic a.n.a.lgesics may be efficacious for the treatment of an acute migraine episode with little to no risk to the fetus.

Table 8.3 Suggested dosage regimens for some commonly used parenteral narcotic a.n.a.lgesic agents for postoperative paina Suggested dosage regimens for some commonly used parenteral narcotic a.n.a.lgesic agents for postoperative paina Agent Dosage Butorphanol 24 mg IM q 34 h, or 0.51 mg IV q 34 h Hydromorphone 12 mg IM q 34 h, or 0.51 mg IV q 3 h Meperidine 50100 mg IM q 34 h Morphine 10 mg (520 mg) IM q 4 h Nalbuphine 10 mg IM or IV q 36 h Pentazocine 30 mg IM or IV q 34 h aRefer to manufacturer's recommendations.

Key references 163.

a.n.a.lgesia following operative procedures The most common indication for acute narcotic a.n.a.lgesic therapy is for postoperative pain relief. Women who require surgery during pregnancy can be safely treated with a variety of a.n.a.lgesic agents for postoperative pain with relative safety for the fetus. Two commonly used regimens are meperidine (Demerol), 50100 mg IM every 34 h, or hydromorphone (Dilaudid), 12 mg every 34 h. Dosage regimens for various parenteral preparations are summarized in Table 8.3.