Part 15 (1/2)
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 (Takahas.h.i.+ 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.