Drugs And Pregnancy Part 32

(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.

EXTERNAL VERSIONS OF BREECH PRESENTATION.

Ritodrine and terbutaline may be used to relax the uterus prior to attempting external version of breech presentations. Preference has been to use terbutaline in a dose of 0.25 mg intravenously. If ritodrine is chosen, a dose of 13 mg intravenously over 2 min should be used (Fernandez et al et al., 1996).

IMMUNOSUPPRESSANTS DURING PREGNANCY.

Immunosuppressants are indicated for use during pregnancy only as therapy for specific life-threatening situations and the majority of cases have no other options. Three primary indications for immunosuppressant use during pregnancy are: (1) organ transplant maintenance; (2) treatment of autoimmune disease; and (3) systemic lupus. Most posttrans-plantation immunosuppressive regimens include prednisone with either azathioprine or cyclosporine. This raises the issue of the possible small risk of cleft palate a.s.sociated with prednisone during pregnancy (see Chapter 13, Use of dermatologics during pregnancy).

Virtually all the known immunosuppressants (Box 15.6), even proximate metabolites of the very large molecule cyclosporine, will cross the placenta (Little, 1997). Neonates are at high risk for a transiently compromised immune system when exposed to the effects of immunosuppressant drug(s). Hence, risk of opportunistic infection is a danger until the infant's immune system recovers following exposure to immunosuppressant therapy.

Long-term effects on the infant's immune system are unknown.

Box 15.6 Immunosuppressant agents Adrenocorticoids Gold salts (Myochrysine, Ridaura, Solganol) Azathioprine (Imuran) Monoclonal antibody Chloroquine (Aralen) Muromonab-CD3 (Orthoclone OKT3) Corticosteroids Tacrolimus Cyclosporine (Samdimmune) 288.

Miscellaneous drugs during pregnancy: tocolytics and immunosuppressants Immunosuppressant agents Immunosuppressant agents Immunosuppressants reduce the immune response by toxicity action on, downregula-tion of, and/or decreased production of immune system components, especially T cells.

Chronic long-term use of immunosuppressants has been a.s.sociated with a higher incidence of neoplastic disease. Relevance of this observation to exposure in utero in utero is unknown. is unknown.

AZATHIOPRINE.

Azathioprine is a 6-mercaptopurine derivative and a purine antimetabolite that acts by suppression of T-lymphocytes and cell-mediated immunity. In vivo In vivo, the drug is metabolized to mercaptopurine. It is used to treat autoimmune diseases and to prevent transplant rejection. Dose-dependent maternal side effects include bone marrow suppression, increased susceptibility to infection, alopecia, rash, gastrointestinal disturbances, arthralgias, hypersensitivity, pancreat.i.tis, and toxic hepat.i.tis (Berkowitz et al et al., 1986).

Among 154 infants born to renal transplant recipients treated with azathioprine and prednisone throughout gestation, congenital anomalies occurred among 9 percent (four of 44) and 6.4 percent (seven of 110), respectively (Penn et al et al., 1980; Registration Committee, 1980). No pattern of anomalies was present. It is not possible to determine whether this rate of congenital anomalies is higher than expected because these mothers took other drugs in addition to azathioprine, and were ill.

Prematurity and fetal growth r.e.t.a.r.dation are increased in frequency among infants born to renal transplant recipients treated with azathioprine compared to infants born to healthy untreated women (Penn et al et al., 1980; Pirson et al et al., 1985; Registration Committee, 1980). The disease process itself (i.e., the need for renal transplantation) may be responsible in part for prematurity and growth r.e.t.a.r.dation. Conditions resulting in chronic renal failure, such as hypertension, diabetes, and other vascular diseases, are also a.s.sociated with an increased frequency of prematurity and/or growth r.e.t.a.r.dation.

An increased frequency of congenital anomalies (limb defects, ocular anomalies, and cleft palate) occurred among the offspring of experimental animals born to mothers treated with azathioprine in doses similar to those used medically in humans (Davison, 1994; Rosenkrantz et al et al., 1967; Tuchmann-Duplessis and Mercier-Parot, 1964; Williamson and Karp, 1981), but not in other studies (Fein et al et al., 1983; Rosenkrantz et et al al., 1967; Tuchmann-Duplessis and Mercier-Parot, 1964).

A case report of fatal neonatal pancytopenia was published of an infant born to a renal transplant recipient treated with azathioprine and prednisone during pregnancy (DeWitte et al et al., 1984). Neonatal lymphopenia and thrombocytopenia were reported in several other children born to women who received similar therapy (Davidson et al et al., 1985; Lower et al et al., 1971; Penn et al et al., 1980; Price et al et al., 1976; Rudolf et al et al., 1979). These disorders are similar to those reported among adults on these medications.

Frequencies of acquired chromosomal breaks and rearrangements were increased in somatic cells of renal transplant recipients receiving azathioprine therapy and, transiently, in the infants of women who were given such treatment during pregnancy (Price et al et al., 1976; Sharon et al et al., 1974). One child with two separate de novo de novo const.i.tutional chromosomal anomalies was born to a woman treated before and during pregnancy const.i.tutional chromosomal anomalies was born to a woman treated before and during pregnancy Immunosuppressants during pregnancy Immunosuppressants during pregnancy 289.

with azathioprine and prednisone (Ostrer et al et al., 1984). Relevance of either observation to clinical situations is unclear. Importantly, chromosome abnormalities in somatic cells cannot be extrapolated to interpret possible gonadal effects.

CYCLOSPORINE.

Cyclosporine is a large molecule (cyclic polypeptide) of fungal origin that is used as an immunosuppressant in the prevention and treatment of allograft rejection. It acts on cell-mediated immunity and T-cell-dependent humoral immunity (Hou, 1989). Cyclosporine, > 1000 in molecular weight, metabolizes to several amino acids ranging from 300 to 500 in molecular weight, that easily cross the placenta, resulting in detectable fetal levels (Claris et al et al., 1993; Lewis et al et al., 1983). Maternal risks of cyclosporine use include hypertension, nephrotoxicity, hepatotoxicity, tremor, hirsutism, paresthesias, seizures, gout, and gingival hypertrophy (Berkowitz et al et al., 1986). Doses of cyclosporine need not be increased during pregnancy to maintain therapeutic levels although body weight and blood volume increase during pregnancy. One study found that cyclosporine doses needed to be lowered during the later stages of pregnancy (Flechner et al et al., 1985).

Cyclosporine has been detected in breast milk, with breastfeeding contraindicated in patients who remain on cyclosporine (Flechner et al et al., 1985). Blood levels of cyclosporine decline to 50 percent at 48 h postpartum and should be undetectable at 1 week (Berkowitz et al et al., 1986). Thus, suppression of the infant's immune system should be short-lived (Rose et al et al., 1989). One report found persistent (13 months) hematologic abnormalities in newborns from renal transplant mothers receiving cyclosporine A, azathioprine, and methylprednisolone (Takahas.h.i.+ et al et al., 1994).

There have been no studies of the frequency of congenital anomalies among infants born to women treated with cyclosporine during pregnancy. The frequency of abortions (spontaneous and induced) and preterm deliveries was higher among cyclosporine-exposed pregnancies (Haugen et al et al., 1994).

The frequency of malformations was not increased among rats and rabbits whose mothers were treated with doses within several multiples of the usual human therapeutic doses of cyclosporine. Maternal toxicity, fetal growth r.e.t.a.r.dation, and intrauterine death were increased in frequency in both species at doses at or just above the maximum used therapeutically in humans (Brown et al et al., 1985; Mason et al et al., 1985; Ryffel et al et al., 1983).

TACROLIMUS.

Tacrolimus is a cyclosporine-like immunosuppressant. It decreases T-cell production by inhibiting enzymes essential to T-cell proliferation. Several small case series or case reports of the use of tacrolimus during pregnancies of transplant patients have been published (Jain et al et al., 1993; Laifer et al et al., 1994; Yos.h.i.+mura et al et al., 1996). There were no malformations and pregnancy outcome was uneventful except for slightly reduced birth weight and transient immunocompromise.

Among 100 pregnancies in women treated with tacrolimus, 71 infants were born and four (5.6 percent) had congenital anomalies (Kainz et al et al., 2000). Another clinical series reported favorable outcomes in pregnancies maintained on tacrolimus (Garcia-Donaire et al et al., 2005). This is no different from the rate in the general population. The frequency of congenital anomalies was not increased among mice exposed to the drug during embryogenesis, although litter weights were slightly reduced (Farley et al et al., 1991).

290.

Miscellaneous drugs during pregnancy: tocolytics and immunosuppressants PREDNISONE AND PREDNISOLONE PREDNISONE AND PREDNISOLONE Corticosteroids are among the most commonly used immunosuppressants. Use of both prednisone, which is metabolized to prednisolone, and prednisolone during pregnancy has been studied intensively (see Chapter 13, Use of dermatologics during pregnancy).

MONOCLONAL ANTIBODY.

T-lymphocyte monoclonal antibodies can eradicate circulating T cells within hours of administration. Acute rejection reactions to organ transplantation can be treated acutely and prophylactically with monoclonal antibodies. Untoward maternal effects include increased vulnerability to infection and neoplasm. Other side effects include tremor, headache, anaphylactic shock, chest pain, hypotension, neurospasm, pulmonary edema, gastrointestinal upset, rash, and allograft vascular thrombosis.

No studies or case reports have been published of congenital anomalies in infants born to mothers treated with this type of agent. According to its manufacturer, it is unknown if muromonab-CD3 is excreted in breast milk.

GOLD COMPOUNDS.

Gold salts act as immunosuppressants via both the humoral and cell-mediated mechanisms, are antirheumatic agents, and cross the placenta (Gimovsky and Montoro, 1991). Patients taking gold compounds should delay conception for 12 months after cessation of therapy.

Fetal exposure to gold compounds has adverse neonatal renal and hemolytic effects.

The frequency of congenital anomalies was not increased among more than 100 infants born to women treated with gold salts during the first trimester (Miyamoto et et al al., 1974). According to the manufacturers, gold compounds were shown to be teratogenic in some but not all animal studies.

CHLOROQUINE.

This antimalarial agent also has some immunosuppressant properties and has been utilized for the treatment of rheumatoid arthritis. It should be avoided in pregnancy if possible (see Chapter 2, Antimicrobials during pregnancy).

SPECIAL CONSIDERATIONS.

Autoimmune disorders 'All autoimmune disorders occur more frequently in women' (Gimovsky and Montoro, 1991). Many women of reproductive age have disorders that require immunosuppressant therapy and clinicians providing care for pregnant women can expect to encounter gravid patients who are receiving immunosuppressant therapy.

Systemic lupus erythematosus Systemic lupus erythematosus (SLE) is rare during pregnancy, ranging from approximately one in 2952 deliveries (Gimovsky and Montoro, 1991; Gimovsky et al et al., 1984) to one in 5000 pregnancies (Tozman et al et al., 1982). It is sometimes first manifested during pregnancy and can adversely affect pregnancy with increases in abortion, prematurity, Special considerations Special considerations 291.

Box 15.7 Indications for steroid therapy in pregnant women with systemic lupus erythematosus (SLE) systemic lupus erythematosus (SLE) Central nervous system involvement Nephritis Hemolytic anemia Pericarditis Leukopenia Pleuritis Myocarditis Thrombocytopenia From Gimovsky and Montoro, 1991.

intrauterine death, and congenital heart block (Gimovsky and Montoro, 1991; Gimovsky et al et al., 1984). Among an estimated 2060 percent of gravid SLE, the disease is exacerbated during pregnancy (Gimovsky et al et al., 1984; Mintz et al et al., 1986; Mor-Yosef et al et al., 1984).

Newborns whose mothers had SLE during pregnancy may manifest a transient lupus-like picture and congenital heart block (Scott et al et al., 1983; Watson et al et al., 1984).

Glucocorticoids are the agents most commonly used to treat SLE during pregnancy (Dombroski, 1989; Gimovsky and Montoro, 1991). It would seem reasonable to continue the patient on steroids if she was on such therapy when the pregnancy was recognized, or if steroids are required during pregnancy (Box 15.7).

Prednisone is the adrenocorticoid most often used to treat patients with SLE. The usual starting dose is 60 mg/day and this can be increased or decreased as needed to control symptoms of the disease (Gimovsky and Montoro, 1991).

It is controversial whether patients should be treated with large-dose steroid therapy at the time of delivery and early postpartum period (Dombroski, 1989). Asymptomatic gravid patients who were not on steroid therapy before the pregnancy will not necessarily require such therapy during pregnancy and postpartum. Steroid dose should be increased during pregnancy for women who are maintained on steroid therapy and who have active disease during gestation. Intravenous hydrocortisone (100 mg) can be given every 68 h during labor and the first 24 h postpartum. Beyond 24 h postpartum, the patient can be returned to her usual maintenance dose of steroids. Low-dose aspirin may be used as necessary throughout pregnancy in patients with lupus anticoagulant.

Other immunosuppressants (e.g., azathioprine, cyclophosphamide an alkylating agent) may be used in pregnant women with SLE exacerbations who are refractory to high-dose steroids. According to the manufacturer, the dose of azathioprine is lower for patients with SLE than for patients with organ transplants. Notably, it is recommended that alkylating agents be avoided in early pregnancy if possible, but they can be used during the second and third trimesters of pregnancy (Glantz, 1994). The antimalarial agent chloroquine has been used to treat SLE and in usual doses (for malaria) carry little risk to the fetus (Dombroski, 1989).

Etiology, pathogenesis, and diagnosis of SLE have been expertly reviewed elsewhere (Gimovsky and Montoro, 1991).

Rheumatoid arthritis Rheumatoid arthritis affects women more frequently than men. It seems common among women of childbearing age, although the prevalence of this disease during 292 292 Miscellaneous drugs during pregnancy: tocolytics and immunosuppressants Box 15.8 Agents utilized for the treatment of rheumatoid arthritis Box 15.8 Agents utilized for the treatment of rheumatoid arthritis Salicylates Salicylates Chloroquinea Nonsteroidal anti-inflammatory agents (NSAIDs) Gold salts Steroids Penicillaminea aNot recommended for use during pregnancy.

Adapted from Gimovsky and Montoro, 1991.