Summary 163.

Other a.n.a.lgesics 160.

Key references 163.

Pregnant women experience a variety of aches and pains and most do not require a.n.a.lgesic therapy. Headaches or pain secondary to dental procedures are common during pregnancy. Many nonnarcotic a.n.a.lgesics are commercially available (many of them over-the-counter medications) and fortunately, with few exceptions, can be utilized safely for the treatment of minor pain during pregnancy.

Limited data are available on the pharmac.o.kinetics of a.n.a.lgesics during pregnancy, and the findings are not entirely consistent. For example, acetaminophen has a decreased half-life and increased clearance in one study, but it is unchanged in another at about the same gestational age (Table 8.1). The pharmac.o.kinetics of meperidine in pregnancy are unchanged compared to nonpregnant controls, and the same is true of the kinetics of meptazinol. In contrast, morphine has a decreased half-life and increased clearance, implying the need for increased frequency or dose regimen to maintain adequate a.n.a.lgesia. Indomethacin has a decreased half-life, C , and C , which also implies dose or frequency regimen adjust-max SS.

ment. In contrast, sodium salicylate has an increased half-life during late pregnancy. Low-dose aspirin does not appear to significantly affect umbilical artery circulation (Owen et al et al., 1993; Veille et al et al., 1993). Notably, the half-life for aspirin increases during pregnancy, implying that a dose decrease in amount and/or frequency may be needed (Table 8.1).

NONSTEROIDAL ANTIINFLAMMATORY AGENTS.

Most of the agents in this group are relatively new a.n.a.lgesics and all are prostaglandin synthetase inhibitors. Some of the commonly used agents in this cla.s.s are listed in Box 8.1. Phenylbutazone and indomethacin are two of the 'oldest' agents in this group.

Box 8.1 Nonsteroidal antiinflammatory agents Phenylbutazone Diflunisal Indomethacin Ketorulac Ibuprofen Piroxicam Fenoprofen Diclofenac Meclofenamate Rofec.o.xib Naproxen Celec.o.xib Tolmentin Etodolac Sulindac 150.

a.n.a.lgesics during pregnancy Table 8.1 Pharmac.o.kinetics a.n.a.lgesic agents during pregnancy: pregnant compared with nonpregnant Agent Pharmac.o.kinetics a.n.a.lgesic agents during pregnancy: pregnant compared with nonpregnant Agent n EGA.

Route AUC.

V.

C.

C.

t Cl PPB.

Control Authors d max SS.

1/2.

(weeks) groupa Acetaminophen 8.3rd trimester PO.

Yes (1) Miners et al. (1986) Acetaminophen 6.36.PO.

Yes (2) Rayburn et al. (1986) Indomethacin 5.3638 IV.

Yes (1) Traeger et al. (1973) Meperidine 18.Term IV.

Yes (1) Kuhnert et al. (1980) Meptazinol 5.3638 IV.

Yes (1) Murray et al. (1989) Morphine 13.Term IM, IV.

Yes (1) Gerdin et al. (1990) Sodium salicylate 20.40.IV.

No Noeschel et al. (1972) Source: Little BB. Obstet Gynecol 1999; 93 93: 858.

EGA, estimated gestational age; AUC, area under the curve; V , volume of distribution; C , peak plasma concentration; C , steady-state concentration; t , half-life; Cl, d max SS.

1/2.

clearance; PPB, plasma protein binding; PO, by mouth; denotes a decrease during pregnancy compared with nonpregnant values; denotes an increase during pregnancy compared with nonpregnant values; = denotes no difference between pregnant and nonpregnant values; IV, intravenous, IM, intramuscular.

aControl groups: 1, nonpregnant women; 2, same individuals studied postpartum; 3, historic adult controls (s.e.x not given); 4, adult male controls; 5, adult male and female controls combined.

Nonsteroidal antiinflammatory agents 151.

Nonnarcotic a.n.a.lgesics SALICYLATES (ASPIRIN).

Aspirin has been used for a variety of therapeutic reasons, but is used primarily as an a.n.a.lgesic, antipyretic, or antiinflammatory agent. Salicylates have been used clinically use for over 100 years and are one of the most commonly used nonnarcotic a.n.a.lgesics.

Aspirin is one of the drugs most used by pregnant women (Corby, 1978; Sibai and Amon, 1988; Streissguth et al et al., 1987). In one prospective study of 1529 pregnant women in 1974 and 1975 (Streissguth et al et al., 1987), almost 50 percent of the women reported taking aspirin, and about 3 percent took it daily. Salicylates are prostaglandin synthetase inhibitors, and act primarily via inactivation of the enzyme cyclo-oxygenase (c.o.x) (Sibai et al et al., 1989), and are well known for inhibiting c.o.x-1 and c.o.x-2 enzymes. Suppression of c.o.x-1 inhibits production of protective esophageal and gastric mucosa, increasing the risk for gastrointestinal bleeds and a.s.sociated complications.

Suppression of c.o.x-1 also inhibits synthesis of vasoactive prostaglandins (prostacyclin and thromboxane A ). Prostacyclin, a potent vasodilator, also inhibits platelet aggrega-2 tion, while thromboxane A , a potent vasoconstrictor, stimulates platelet aggregation 2 (Bhagwat et al et al., 1985; Ellis et al et al., 1976). Prostaglandin E and prostaglandin F are also 2 inhibited. In usual human therapeutic doses, aspirin results in 'nonselective inhibition of prostaglandin synthetase in various tissues' (Sibai and Amon, 1988), thus suppressing c.o.x-2. Suppression of c.o.x-2 has an a.n.a.lgesic effect by blocking prostaglandins a.s.sociated with inflammation.

High or normal doses (>325 mg) block production of prostacyclin and thromboxane, and low-dose aspirin (6083 mg) results in selective block of thromboxane production, and favors the prostacyclin (vasodilation) pathway (Beaufils et al et al., 1985; Masotti et al et al., 1979; Schiff et al et al., 1989; Sibai et al et al., 1989; Spitz et al et al., 1988; Wallenberg, 1995; Wallenberg et al et al., 1986). This provides the basis for the use of low-dose aspirin to fore-stall or prevent pregnancy-induced hypertension (Gant and Gilstrap, 1990) (see Special considerations). Importantly, low-dose aspirin does not completely inhibit thromboxane and does not completely 'spare' prostacyclin. One group of investigators found that 81 mg of aspirin inhibited thromboxane by 75 percent, but also inhibited prostacyclin by approximately 20 percent (Spitz et al et al., 1988).

There have been several large studies regarding the effect of aspirin on preeclampsia (Hauth et al et al., 1993; Sibai et al et al., 1993), as well as a meta-a.n.a.lysis, Collaborative Low-Dose Aspirin Study in Pregnancy (CLASP, 1994). These results indicate that low-dose aspirin does decrease the incidence of preeclampsia (Hauth and Cunningham, 1995).

Review of four large controlled trials that included over 13 000 pregnant women led to the conclusion that daily low-dose aspirin significantly reduced the risk of preeclampsia (Wallenberg, 1995). In a follow-up study, compared to untreated women, aspirin-treated women had: (1) a greater than twofold longitudinal reduction in serum thromboxane B2 levels; (2) a significantly decreased frequency of preeclampsia; and (3) fewer premature and growth-stunted newborns (Hauth et al et al., 1995a).

Aspirin readily crosses the placenta and results in physiologically significant fetal levels (Levy et al et al., 1975; Palminsano and Ca.s.sudy, 1969; Turner and Collins, 1975). Aspirin has been reported to be teratogenic in various laboratory animals when given at several times the human adult dose (Wilson et al et al., 1977), and there have been anecdotal case 152 152 a.n.a.lgesics during pregnancy reports of congenital anomalies in humans (Agapitos et al et al., 1986). However, the risk of congenital anomalies in infants of mothers exposed to aspirin in the first 16 weeks of pregnancy was not increased when compared to unexposed infants (Slone et al et al., 1976).

The major malformation rate in a large national study in the USA was 6.7 percent for heavy aspirin use, 6.8 percent for intermediate use, and 6.3 percent for women who did not use aspirin (Heinonen et al et al., 1977). Among 144 pregnant women who were 'heavy aspirin' users, the frequency of major birth defects in offspring was 4.2 percent not significantly different from that in the general population (3.55 percent; Turner and Collins, 1975). Similarly, among 62 women who used aspirin in the first trimester, the rate was not significantly higher than that expected in the general population (Aselton et et al al., 1985).

High-dose aspirin taken late in the third trimester may be a.s.sociated with (1) closure of the ductus arteriosus, (2) persistent pulmonary hypertension (Levin et al et al., 1978; Sibai and Amon, 1988), (3) decreased fetal renal function, and (4) oligohydramnios (Witter and Niebyl, 1986). Lower IQs in offspring of mothers who took aspirin in the first trimester of pregnancy have been reported by some investigators (Streissguth et al et al., 1987), but not others (Klebanoff and Berendes, 1988). Maternal use of high-dose aspirin is a.s.sociated with increased frequency of post-term pregnancies (Collins and Turner, 1975), low birth weight (Lewis and Schulman, 1973), neonatal bleeding disorders, and intracranial hemorrhage in premature infants (Rumack et al et al., 1981; Stuart et al et al., 1982), and premature closure of the ductus arteriosus in the fetus (Levin et al et al., 1978). However, these complications are not a.s.sociated with aspirin use when pharmacologically controlled doses of salicylates were used (Sibai and Amon, 1988). This implies that gravidas may be self-adjusting their doses and/or frequency regimens upward, increasing the risk of untoward outcomes.

There were no significant differences in the frequency of congenital anomalies, motor or developmental delay, or height or weight between those exposed to low-dose aspirin and controls at 12- and 18-month follow-up (CLASP, 1995).

In one study, a significantly increased frequency of placental abruption was found among women taking low-dose aspirin therapy compared to controls (Sibai et al et al., 1993). However, meta-a.n.a.lysis of 11 clinical trials found no significant difference in the incidence of placental abruption among women taking aspirin compared to controls (Hauth et al et al., 1995b).

In summary, aspirin at therapeutic or low doses is not a.s.sociated with a significant risk of birth defects, although in very large, chronic doses close to the time of delivery, aspirin may be a.s.sociated with an increase in bleeding disorders in the mother and fetus.

ACETAMINOPHEN.

Acetaminophen is also commonly used during pregnancy, second only to aspirin. Forty-one percent of pregnant women reported acetaminophen use during pregnancy in a large longitudinal study (Streissguth et al et al., 1987). The frequency of congenital birth defects in several studies was not increased above background among more than 1200 offspring whose mothers used acetaminophen during the first trimester (Aselton et al et al., 1985; Heinonen et al et al., 1977; Jick et al et al., 1981). The IQs of offspring at 4 years of age whose mothers had ingested acetaminophen during pregnancy were no different than controls (Streissguth et al et al., 1987).

Nonsteroidal antiinflammatory agents 153.

The potential a.s.sociation of maternal acetaminophen use and polyhydramnios is unclear, but is based upon one case report of one single infant (Char et al et al., 1975).

Ingestion of large doses of acetaminophen or the protracted use of this drug may result in renal and hepatic failure in the adult and could result in the same complications in the fetus (see Chapter 14).

In summary, acetaminophen is one of the safest nonnarcotic a.n.a.lgesics available for use in the pregnant woman when doses are kept in the therapeutic range.

PHENACETIN.

Phenacetin is an a.n.a.lgesic and antipyretic with poor antiinflammatory activity. It is often used in combination with other a.n.a.lgesics, and one of its major metabolites is acetaminophen. The frequency of malformations was not increased among more than 18 000 offspring of mothers who utilized this a.n.a.lgesic either alone or in combination with other agents (Heinonen et al et al., 1977; Jick et al et al., 1981). There are also no reports of this a.n.a.lgesic being teratogenic in animals.

PHENYLBUTAZONE.

Phenylbutazone is a nonsteroidal antiinflammatory agent (NSAID) with a.n.a.lgesic, antipyretic, and antiinflammatory actions. It is commonly used to treat women with arthritic conditions (rheumatoid arthritis, degenerative joint disease). No scientific studies are published regarding the safety and efficacy of this medication in pregnant women.

Two major congenital anomalies were among 27 infants exposed to phenylbutazone, but these data were not peer reviewed (Rosa, personal communication, cited in Briggs et al. et al. , 2005). Some of the prostaglandin synthetase inhibitors are a.s.sociated with premature closure of the ductus arteriosus in the newborn (Csaba , 2005). Some of the prostaglandin synthetase inhibitors are a.s.sociated with premature closure of the ductus arteriosus in the newborn (Csaba et al et al., 1978; Levin et al et al., 1978), and theoretically phenylbutazone could also be a.s.sociated with this complication. However, there are no reports of this to date.

INDOMETHACIN.

Indomethacin has antipyretic action in addition to a.n.a.lgesic and antiinflammatory effects.

It is used for the treatment of rheumatoid arthritis and osteoarthritis, bursitis, and ten-donitis. It has also been used to treat premature labor in the second and third trimesters of pregnancy (Niebyl et al et al., 1980; Sibony et al et al., 1994; Zuckerman et al et al., 1974, 1984). In addition, intravenous indomethacin has been used to close a hemodynamically significant patent ductus arteriosus in premature infants. Indomethacin has also been used for the treatment of symptomatic leiomyomata during pregnancy (Dildy et al et al., 1992).

The frequency of congenital anomalies among more than 400 infants following exposure to indomethacin during the first trimester is no different from the population background rate (Aselton et al et al., 1985; Kallen, 1998). Congenital anomalies have also not been found to be increased in several reports in which animals received several times the adult human dose of indomethacin (Kalter, 1973; Klein et al et al., 1981; Randall et al et al., 1987).

Indomethacin is a.s.sociated with premature closure of the ductus arteriosus and pulmonary hypertension in the fetus and newborn in several reports (DeWit et al et al., 1988; Levin et al et al., 1978; Manchester et al et al., 1976; Moise et al et al., 1988). Ductal constriction was found by echocardiography in seven of 14 fetuses in 13 pregnant women who received indomethacin for premature labor at 2531 weeks gestation (Moise et al et al., 1988). Ductal 154 154 a.n.a.lgesics during pregnancy constriction was transient and resolved within 24 h after discontinuation of the indomethacin. Fetal ductus arteriosus closure in the fetus was also a.s.sociated with indomethacin exposure in several animal models (Harker et al et al., 1981; Harris, 1980; Levin et al et al., 1979). No evidence was reported of either premature closure of the ductus arteriosus or pulmonary hypertension in 15 fetuses whose mothers had received indomethacin in a randomized trial (Niebyl et al et al., 1980). A review of 167 newborns [<35 weeks="" estimated="" gestational="" age="" (ega)]="" whose="" mothers="" received="" indomethacin="" for="" tocolysis="" found="" no="" cases="" of="" premature="" closure="" of="" the="" ductus="" arteriosus="" or="" persistent="" fetal="" circulation="" (dudley="" et="" al="" et="" al.,="">

Among 818 women who received indomethacin during pregnancy near the time of delivery, perinatal complications occurred in 13 percent compared to 1.8 percent for controls (Marpeau et al et al., 1994). A study of 57 infants born at 30 weeks EGA reported an increase in necrotizing enterocolitis, intracranial hemorrhage, and patent ductus arteriosus compared to 57 infants not exposed to indomethacin (Norton et al et al., 1993), paralleling adverse neonatal outcomes shown in numerous other studies (Eronen et al et al., 1994; Major et al et al., 1994; Rasenen and Jouppila, 1995; van der Heijden et al et al., 1994). In contrast, among 15 infants exposed to indomethacin chronically during gestation, no instances of patent ductus occurred (Al-Alaiyan et al et al., 1996).

IBUPROFEN.

Ibuprofen is another commonly used NSAID a.n.a.lgesic. The frequency of congenital anomalies was no greater than expected among 51 infants whose mothers took ibuprofen during the first trimester of pregnancy (Aselton et al et al., 1985). In a case series, five infants were reported with abnormalities at birth, but no distinct anomaly syndrome (Barry et al et al., 1984). Ibuprofen was also a.s.sociated with decreased amniotic fluid volume (Hickok et al et al., 1989).

MECLOFENAMATE.

Among 166 infants exposed to meclofenamate during the first trimester, the frequency of congenital anomalies (3.6 percent) was not greater than expected in the general population (3.55 percent), but the study was neither peer reviewed nor controlled (Rosa, personal communication, cited in Briggs et al. et al. , 2005). , 2005).

NAPROXEN.

In a series of children born to 23 women who took naproxen throughout pregnancy for rheumatic disease, no congenital anomalies were found (Ostensen and Ostensen, 1996).

SULINDAC.

The frequency of major congenital anomalies was 4.3 percent among 69 infants born to women who used sulindac during the first trimester, and is within the range of that expected in the general population, i.e., 3.55 percent (Rosa, personal communication, cited in Briggs et al. et al. , 2005). However, this study is neither peer reviewed nor controlled. , 2005). However, this study is neither peer reviewed nor controlled.

Sulindac is another NSAID that has been used as a tocolytic. In comparisons of sulindac to indomethacin for tocolysis, two studies found that sulindac was as effective as indomethacin but had fewer side effects (Carlan et al et al., 1992; Rasenen and Jouppila, 1995).

Nonsteroidal antiinflammatory agents 155.

Miscellaneous NSAIDS No reports have been published regarding the other NSAID a.n.a.lgesics sometimes used during pregnancy: fenoprofen, tolmentin, rofec.o.xib, celec.o.xib, and etodolac. However, all of these drugs are prostaglandin synthetase inhibitors and could theoretically cause premature closure of the ductus arteriosus and/or oligohydramnios.

ROFEc.o.xIB.

Rofec.o.xib is a cyclooxygenase-2 (c.o.x-2) selective a.n.a.lgesic. No studies of congenital anomalies in offspring exposed to rofec.o.xib during embryogenesis have been published.

Premature closure of the ductus arteriosus is a theoretical risk of maternal therapy with rofec.o.xib because of the pharmacologic action of the drug. Rofec.o.xib (Vioxx) was with-drawn from the market in September 2004 because an increased risk of myocardial infarction or stroke was found.

CELEc.o.xIB.

Celec.o.xib is a c.o.x-2 selective a.n.a.lgesic. No studies of congenital anomalies in infants exposed to celec.o.xib during organogenesis have been published. Premature closure of the ductus arteriosus is a theoretical risk because of the pharmacologic action of celec.o.xib.