Part 32 (2/2)
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.
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