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pregnancy is unknown. Up to two-thirds of the patients with rheumatoid arthritis experience marked improvement during pregnancy (Neely and Persellin, 1977; Ostensen and Husby, 1983; Unger et al et al., 1983), suggesting that pregnancy may improve the symptoms of rheumatoid arthritis.

The mainstay of therapy for both pregnant and nonpregnant women with rheumatoid arthritis is aspirin (Box 15.8). To achieve therapeutic blood levels of 1525 mg/dL, patients may require up to 4 g of salicylates daily (Thurnau, 1983). However, during pregnancy lower doses of salicylates (up to 3 g per day) are recommended. Large-dose salicylate therapy during pregnancy could cause hemorrhagic complications in the fetus, because salicylates cross the placenta. These complications may also occur in newborns and/or mothers.

Nonsteroidal antiinflammatory agents (NSAIDs) can be used in pregnant women with rheumatoid arthritis. These agents can be a.s.sociated with mild to moderate oligohydramnios, premature closure of the ductus arteriosus and persistent fetal circulation, as well as intracranial hemorrhage in the neonate (Chapter 8, a.n.a.lgesics during pregnancy). Chloroquine, as a mild immunosuppressant, has been used to treat rheumatoid arthritis and SLE, but because of low efficacy it is generally not recommended to treat pregnant women who have rheumatoid arthritis.

Penicillamine (Cuprimine) is used for rheumatoid arthritis, but should not be used during pregnancy. It is a chelating agent used in lead poisoning. However, its mechanism of action as an antirheumatoid agent is not understood. It crosses the placenta and is contraindicated for use during pregnancy because it interrupts fetal collagen formation (Gimovsky and Montoro, 1991) and is considered a human teratogen (Shepard, 1989).

Immunosuppressant drugs such as cyclosporine and azathioprine are used to treat rheumatoid arthritis in nonpregnant patients (Kerstens et al et al., 1995; Kruger and Schattenkirchner, 1994). These agents should be reserved to treat pregnant women with severe disease refractory to more commonly used agents with which there is greater clinical experience and published data.

Organ transplantation Progress in organ transplantation and pharmacological therapy over the past three decades is significant. Occurrence of renal transplantation and subsequent pregnancy is increasing, and the literature on the subject is growing.

Renal transplantation Among more than 800 pregnancies (from seven reports) after renal transplantation, there were 0.5 percent maternal deaths, 68 percent miscarriages, 1220 percent therapeutic Special considerations Special considerations 293.

abortions, 1 percent stillbirths, and 2 percent neonatal deaths (Hou, 1989; Radomski et et al al., 1995). Three first-line medications are used to prevent rejection following renal transplantation: corticosteroids, azathioprine, and cyclosporine. Corticosteroid, cyclosporine, azathioprine, and tacrolimus therapy have been discussed above.

Cyclosporine is key to decreasing the frequency of renal transplant rejection, especially of cadaver kidneys (Hou, 1989). This immunosuppressant agent's metabolites cross the placenta. If the situation is life threatening, the benefits of its use clearly outweigh any risks. Fetal growth r.e.t.a.r.dation was reported in infants whose mothers used cyclosporine (Hou, 1989; Pickrell et al et al., 1988; Radomski et al et al., 1995), but it is not possible to differentiate drug effects from the renal disease being treated (e.g., chronic hypertension is a concomitant complication).

Pregnant women should be counseled for the increased risks of both maternal and fetal infection, and the possible increased risk of genital carcinoma a.s.sociated with immunosuppressant therapy (Kossay et al et al., 1988). Notably, women who have symptoms of rejection within 3 months of delivery usually progress to loss of the renal transplant within the next 24 months. The medical significance of the correct immunosuppressant therapy during pregnancy is emphasized by these sequelae.

Other organ transplantation Several reports of pregnancies following liver, heart and heartlung, and bone marrow transplants have been published (Deeg et al et al., 1983; Kallen et al et al., 2005; Key et al et al., 1989; Kossay et al et al., 1988; Lowenstein et al et al., 1988; Miniero et al et al., 2004; Newton et al et al., 1988; Rose et al et al., 1989; Walcott et al et al., 1978). Immunosuppressant therapy, especially with regard to cyclosporine, is utilized similarly with other organ transplants as with renal transplantation. Among 152 infants born after transplantation, a high frequency of preeclampsia (22 percent), preterm birth (46 percent), low birthweight (41 percent), infants small for gestational age (16 percent), and infant death were found for deliveries after transplantation. Congenital anomalies were not increased in frequency (Kallen et al et al., 2005).

Heart transplantation More than 40 infants have been born to women with heart transplants (Miniero et al et al., 2004; Radomski et al et al., 1995; Scott et al et al., 1993). Mothers were treated with cyclosporine or azathioprine throughout gestation. Signs of organ rejection occurred in about one-quarter of mothers, and about one-third of infants were of low birthweight and premature. The pregnancies, mothers' postpartum, and neonatal course were complicated by infection.

Liver transplantation Among 38 pregnancies to 29 women with liver transplants, 13 percent of mothers had signs of organ rejection (Radomski et al et al., 1995). There were 31 live births (eight abortions) and 32 percent were of low birthweight, with 39 percent premature. Slightly more than one-quarter of the pregnancies were complicated by infection. Among 15 infants born after liver transplantation, two were malformed (Kallen et al et al., 2005).

294.

Miscellaneous drugs during pregnancy: tocolytics and immunosuppressants Box 15.9 Agents utilized for the treatment of inflammatory bowel Box 15.9 Agents utilized for the treatment of inflammatory bowel disease disease Ulcerative colitis Crohn's disease 5-aminosalicylic acid 6-mercaptopurine 6-mercaptopurine Azathioprine Azathioprine Cyclosporine Prednisone Prednisone Sulfasalazine Inflammatory bowel disease Two of the most common forms of inflammatory bowel disease are ulcerative colitis and Crohn's disease (regional enteritis). The etiology of these diseases is unknown.

Corticosteroids (i.e., prednisone) have been used for the active stages of both diseases (Box 15.9). Sulfasalazine and 5-aminosalicylic acid have also been used successfully for the treatment of ulcerative colitis during pregnancy (Cunningham, 1994; Habal et al et al., 1993).

Refractory cases of ulcerative colitis and Crohn's disease during pregnancy are an indication for immunosuppressive drugs, such as azathioprine and 6-mercaptopurine (Cunningham, 1994). In a meta-a.n.a.lysis of azathioprine and 6-mercaptopurine to treat Crohn's disease, both drugs were effective in treating active disease and for maintaining remission (Pearson et al et al., 1995), but efficacy during pregnancy was not studied. Agents utilized for the treatment of inflammatory bowel disease (Box 15.9) include cyclosporine for the treatment of Crohn's disease (Brynskov et al et al., 1989). It seems reasonable to reserve these more potent immunosuppressants for pregnant women refractory to steroid therapy.

Multiple sclerosis Immunosuppressants are used to treat secondary, progressive, and relapsing multiple sclerosis. The agents currently used are azathioprine, cyclophosphamide, cyclosporine, and methotrexate. Treatment of multiple sclerosis relapse with immunosuppressants is controversial. Treatment of multiple sclerosis with these drugs during pregnancy carries a risk of birth defects similar to use of the drug for other purposes. However, it should be noted that potential for adverse effects decreases as the dose is lowered (e.g., cyclophosphamide 'booster' doses).

SUMMARY.

Immunosuppressant agents are used in pregnant women to treat a variety of diseases, including collagen-vascular disease and organ transplantation. Steroids, azathioprine, and cyclosporine are the agents most frequently used to treat collagen-vascular disease and organ transplantation, and apparently can be used in pregnant women with minimal risk to the fetus. Steroids seem to pose little or no risk to intrauterine development after the first trimester or to the mothers. Azathioprine and cyclosporine have not been Key references Key references 295.

studied adequately, and exposure in the first trimester has not been adequately a.s.sessed.

However, organ transplant rejection is life-threatening and any risk is outweighed by the benefit.

Key references Garcia-Donaire JA, Acevedo M, Gutierrez MJ et al. Tacrolimus as basic immunosuppression in pregnancy after renal transplantation. A single-center experience. Transplant Proc 2005; 37 37: 3754.

Idama TO, Lindow SW. Magnesium sulphate. A review of clinical pharmacology applied to obstetrics. Br J Obstet Gynaecol 1998; 105 105: 260.

Johnson KA, Mason GC. Severe hypotension and fetal death due to tocolysis with nifedipine.

BJOG 2005; 112 112: 1583.

Kainz A, Harabacz I, Cowlrick IS et al. Review of the course and outcome of 100 pregnancies in 84 women treated with tacrolimus. Transplantation 2000; 70 70: 1718.

Kallen B, Westgren M, Aberg A, Olausson PO. Pregnancy outcome after maternal organ transplantation in Sweden. BJOG 2005; 112 112: 904.

Kandysamy V, Thomson AJ. Severe hypotension and fetal death due to tocolysis with nifedipine. BJOG 2005; 112 112: 1583.

Leveno KL, Little BB, Cunningham FG. National impact of tocolytic therapy on low birth weight. Obstet Gynecol 1990; 76 76: 12.

Little BB. Immunosuppressant therapy during gestation. Semin Perinatol 1997; 21 21: 143.

Miniero R, Tardivo I, Centofanti P et al. Pregnancy in heart transplant recipients. J Heart Lung Transplant 2004; 23 23: 898.

Tsukahara H, Kobata R, Tamura S, Mayumi M. Neonatal bone abnormalities attributable to maternal administration of magnesium sulphate. Pediatr Radiol 2004; 34 34: 673.

van Veen AJ, Pelinck MJ, van Pampus MG, Erwich JJ. Severe hypotension and fetal death due to tocolysis with nifedipine. BJOG 2005; 112 112: 509.

Yos.h.i.+mura N, Oka T, Fujiwara Y, Ohmori Y, Yasumura T, Honjo H. A case report of pregnancy in renal transplant recipient treated with FK506 (tacrolimus). Transplantation 1996; 61 61: 1552.