Part 32 (1/2)

(see Box 15.2). Severe maternal cardiovascular complications occurred among nearly 5 percent of women treated with terbutaline (Katz et al et al., 1981). The risk of pulmonary edema among women receiving ritodrine or other beta-mimetics is increased with certain maternal complications: infection, excessive intravenous hydration, multifetal gestation, underlying cardiac disease increase (ACOG, 1995).

Beta-mimetics also alter glucose tolerance and have been a.s.sociated with ketoacidosis among women with poorly controlled insulin-dependent diabetes. Maternal deaths have also been reported with the use of beta-mimetic therapy.

Fetal effects Fetal tachycardia and arrhythmias are a.s.sociated with beta-mimetic therapy, including ritodrine (Barden et al et al., 1980; Hermansen and Johnson, 1984). Protracted ritodrine therapy has been a.s.sociated with increased septal thickness in exposed neonates (Nuchpuckdee et al et al., 1986). However, these do not appear to be frequent complications of ritodrine, or beta-mimetic, therapy in general.

Beta-sympathomimetic tocolytic therapy, including ritodrine, was a.s.sociated with a 2.5-fold increased risk of periventricular-intraventricular hemorrhage (Groome et al et al., 1992). However, grades 3 and 4 hemorrhages were not increased. In another investigation, no a.s.sociation of ritodrine with intraventricularperiventricular hemorrhage was found (Box 15.3) (Ozcan et al et al., 1995).

Beta-mimetics are generally not used during the period of organogenesis, with the exception of terbutaline for asthma. No reports of teratogenic effects of ritodrine in the human have been published. An increased frequency of cardiovascular anomalies in chick embryos exposed to ritodrine and terbutaline was found in one study, and it was concluded that teratogenic effects were secondary to stimulation of beta-2-adrenergic receptors (Lenselink et al et al., 1994). The significance of these findings to human pregnancies is unknown.

TERBUTALINE.

Although terbutaline has not been approved by the FDA for the specific indication of premature labor, it is probably the most commonly used beta-mimetic for this purpose.

Interestingly, according to its manufacturer, it should not be used for tocolysis.

Terbutaline has also been utilized in the management of symptomatic placenta previa in pregnancies remote from term (Besinger et al et al., 1995), for the management of uterine hypotonus, especially in the presence of a nonrea.s.suring fetal heart rate pattern (Smith, 1991) and for inducing uterine relaxation prior to attempting external cephalic version (Fernandez et al et al., 1996).

Neonatal myocardial dysfunction and necrosis have been a.s.sociated with terbutaline tocolytic therapy (Fletcher et al et al., 1991; Thorkelsson and Loughead, 1991), but the causal relations.h.i.+p to the maternal therapy is controversial (Bey et al et al., 1992; Kast and Hermer, 1993). Neonatal hypoglycemia and fetal tachycardia were a.s.sociated with terbutaline tocolytic therapy late in pregnancy (Peterson et al et al., 1993; Roth et al et al., 1990; Sharif et al et al., 1990), but these effects were transient. Neonatal behavior was transiently altered among the infants of pregnant women who received terbutaline tocolysis (Thayer and Hupp, 1997).

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Miscellaneous drugs during pregnancy: tocolytics and immunosuppressants Maternal effects Maternal effects Terbutaline may be a.s.sociated with maternal cardiovascular effects (including pulmonary edema) similar to those a.s.sociated with ritodrine (Katz et al et al., 1981). One review of cardiopulmonary effects of low-dose continuous terbutaline infusion in 8709 women found 47 women (0.5 percent) developed one or more adverse cardiopulmonary effects.

Twenty-eight women (0.3 percent) developed pulmonary edema (Perry et al et al., 1995). In another review of 1000 women given a combination of intravenous terbutaline and magnesium sulfate, the side effects of protracted therapy were negligible (Kosasa et al et al., 1994).

Two cases of terbutaline hepat.i.tis in pregnancy have been reported (Quinn et al et al., 1994).

ETHANOL.

Alcohol is not recommended for use during pregnancy as it is a.s.sociated with both teratogenic and fetal effects. This agent is reviewed in detail in Chapter 16, Substance abuse during pregnancy.

MAGNESIUM SULFATE.

Magnesium sulfate inhibits uterine contractions by apparently antagonizing calcium flow into the myometrial cell. Magnesium sulfate has no proven efficacy in delaying delivery beyond 2448 h (Cotton et al et al., 1984; c.o.x et al et al., 1990; Kimberlin et al et al., 1996), as with other tocolytic agents.

Maternal effects Hypermagnesemia (cutaneous flus.h.i.+ng, nausea, vomiting, respiratory depression, intracar-diac conduction delays) is the major maternal adverse effect of magnesium sulfate therapy.

Respiratory arrest is frequent when MgSO levels reach 12 mEq/L or greater. Protracted ther-4 apy (many days) with magnesium sulfate for preterm labor increases calcium loss and may decrease bone mineralization (Smith et al et al., 1992). Bleeding time during pregnancy may be prolonged with magnesium sulfate therapy, but this is not clinically significant (Fuentes et al et al., 1995). Unlike ritodrine, magnesium sulfate is not a.s.sociated with a 'peripheral vascular steal'

syndrome and does not decrease placental perfusion (Dowell and Forsberg, 1995).

Fetal effects Magnesium sulfate crosses the placenta and, in extremely large doses, may cause neonatal cardiorespiratory depression and transient loss of beat-to-beat variability (Hallak et et al al., 1999; Hiett et al et al., 1995; Idama and Lindow, 1998; Wright et al et al., 1996) . . Calcium gluconate can reverse these symptoms if they become severe. Calcium gluconate can reverse these symptoms if they become severe.

Osseous lesions (metaphyses, costochondral junctions, skull) have been reported among infants born to women treated with magnesium sulfate for more than a week prior to delivery (Malaeb et al et al., 2004; Tsukahara et al et al., 2004), but they are resorbed within months of life (Santi et al et al., 1994; Tsukahara et al et al., 2004).

Nonsteroidal antiinflammatory agents INDOMETHACIN.

Indomethacin is a prostaglandin synthetase inhibitor that has been used to delay labor (Carlan et al et al., 1992; Niebyl et al et al., 1980; Zuckerman et al et al., 1974). Indomethacin is effi-Tocolytics 285.

cacious as a tocolytic for short periods of time (Niebyl et al et al., 1980), but it may be a.s.sociated with significant adverse fetal effects: oligohydramnios, ductus arteriosus constriction, persistent fetal circulation, neonatal hypertension, intracranial hemorrhage, necrotizing enterocolitis, anemia, cystic renal changes, neonatal death (Csapo et al et al., 1978; Goldenberg et al et al., 1989; Manchester et al et al., 1976; Moise et al et al., 1988; Norton et al et al., 1993; Rubattelli et al et al., 1979; Rudolph, 1981; van der Heijden et al et al., 1994).

Maternal effects Indomethacin resulted in few maternal side effects when used as a tocolytic. Potential adverse effects include: interst.i.tial nephritis, acute renal failure, peptic ulcer disease, decrease in platelets, prolonged bleeding time (Clive and Stoff, 1984; Lunt et al et al., 1994; Norton et al et al., 1993). It may exacerbate hypertension (Gordon and Samuels, 1995).

Among 83 women who received indomethacin during pregnancy, no adverse maternal or fetal effects were noted, except for oligohydramnios, which resolved spontaneously (Sibony et al et al., 1994).

Fetal effects In a review of 28 studies including 1621 infants exposed to indomethacin for tocolysis, the risk for adverse neonatal outcomes was not increased (Loe et al et al., 2005). However, there were only three randomized clinical trials included and one of them did find an increased risk for adverse neonatal outcomes a.s.sociated with indomethacin tocolysis.

SULINDAC.

Sulindac is another prostaglandin synthetase inhibitor, similar to indomethacin. It has been used to treat preterm labor. Sulindac was as effective as indomethacin, but with fewer adverse fetal effects in a randomized prospective study of 36 women in preterm labor (Carlan et al et al., 1992). No epidemiological studies of sulindac during pregnancy have been published, but it is probably a.s.sociated with potential adverse effects similar to indomethacin.

Calcium channel blockers NIFEDIPINE.

Nifedipine is a calcium channel blocker which promotes smooth muscle relaxation by reducing intracellular calcium. It is also a cardiovascular agent because of its vasodilat-ing effects. Owing to smooth muscle relaxation, there may be maternal hypotension and subsequent decreased uteroplacental perfusion, although in human studies there has been no evidence that nifedipine compromises the fetus (Ray and Dyson, 1995).

In a preliminary study of nifedipine versus ritodrine, it was suggested that nifedipine was a.s.sociated with fewer maternal and fetal side effects (van Dijk et al et al., 1995). A recent case report of severe hypotension and fetal death a.s.sociated with nifedipine, tocolysis-ascribed causality (van Veen et al et al., 2005) has led to the suggestion that the a.s.sociation may not be causal (Johnson and Mason, 2005; Kandysamy and Thomson, 2005; Papatsonis et al et al., 2005).

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Miscellaneous drugs during pregnancy: tocolytics and immunosuppressants VERAPAMIL VERAPAMIL As discussed in Chapter 3, verapamil is used as an antiarrhythmic, antihypertensive, and tocolytic agent. No epidemiologic studies on the safety of this agent during pregnancy have been published. Maternal hypotension and resultant decreased uterine blood flow are the major risks from the use of this agent.

OXYTOCIN ANTAGONISTS.

Atosiban inhibits oxytocin-induced uterine contractions. It is a nonapeptide oxytocin a.n.a.log with compet.i.tive oxytocin antagonist actions. Consistent reduction in uterine activity during the infusion of atosiban has been observed (Goodwin et al et al., 1995). No studies regarding the safety of this agent have been published, but a review is available (Shubert, 1995).

NITRIC OXIDE DONOR DRUGS.

Among 13 women given nitroglycerin patches, the drug was effective in preventing preterm birth, but maternal side effects involved hypotension and sedation (Lees et al et al., 1994).

No difference in tocolytic efficacy was noted in a randomized investigation compar-ing intravenous nitroglycerin with magnesium sulfate (Clavin et al et al., 1996). Parenteral nitroglycerin is a.s.sociated with severe maternal hypotension, which suggests that placental hypoperfusion may be a serious risk.

Special considerations Tocolytic therapy is controversial. Concern includes efficacy of specific agents and whether these agents can effectively delay labor for greater than 48 h, i.e., for 1 week or longer. Tocolytics do appear to be effective for delaying labor for short intervals (2448 h) and possibly for relieving hypertonic contractions. This may be of benefit with regard to corticosteroid therapy in an attempt to accelerate fetal lung maturation.

PREMATURE LABOR.

The most commonly used agents for treating premature labor are: ritodrine, terbutaline, and magnesium sulfate. The usual doses of ritodrine and terbutaline are shown in Boxes 15.4 and 15.5, respectively.

Magnesium sulfate treatment is an initial loading intravenous dose of 4 g of a 20 percent solution, followed by an infusion of 23 g/h until uterine contractions stop (c.o.x et et al al., 1990). Infusions are usually continued for 1224 h.

Box 15.4 Protocol for intravenous ritodrinea Initial, 50100 g/min Incremental increases, 50 g/min every 20 min Maximum dose, 350 g/min aSee manufacturer's recommendations.

Immunosuppressants during pregnancy 287.

Box 15.5 Protocol for terbutaline Intravenous Subcutaneous Initial, 2.5 mg/min Dose, 250 g every hour until contractions stop Increases, 2.5 mg/min every 20 min Oral Maximum, 20 mg Dose, 2.55 mg q 46 h Indomethacin is given in an initial oral dose of 100 mg followed by 25 mg orally every 4 h for 48 h (Carlan et al et al., 1992). Sulindac is given in an oral dose of 200 mg every 12 h for 48 h (Carlan et al et al., 1992).

UTERINE HYPERTONUS OR 'FETAL DISTRESS'

The usual ritodrine dose in this clinical setting is an intravenous bolus of 13 mg over 2 min, and for terbutaline, 0.25 mg subcutaneously or intravenously (Smith, 1991).

Magnesium sulfate can also be given in a 4 g intravenous bolus.