Immunosuppression in pregnant women with systemic lupus erythematosus

Abstract

Most pregnancies are successful in women with systemic lupus erythematosus, particularly if the disease is quiescent and there are no signs of active nephritis. There is no major impact of immunosuppression on maternal outcome. However, high doses of cyclosporine and glucocorticoids are used which may favor development of hypertension or preeclampsia. Some immunosuppressive drugs may exert toxic effects on the fetus. Glucocorticoids may cause small birth weight, and azathioprine and calcineurin inhibitors may be associated with lower birth weight, gestational age and prematurity. Cyclophosphamide may cause fetal malformation when given in the first trimester. Mycophenolate and leflunomide are teratogenic drugs and should be withdrawn before conception in case of programmed pregnancy or should be rapidly discontinued in case of unexpected pregnancy. Option counseling for pregnancy and correct use of immunosuppressive drugs are prerequisites for a successful pregnancy in women with lupus.

Keywords:

• autoimmune diseases
• immunosuppression
• lupus nephritis
• pregnancy
• systemic lupus erythematosus
• teratogenic drugs

Today, pregnancy is no longer considered as a contraindication in women with lupus. The outcome is usually good for the mother, when the disease is quiescent. Even in pregnant women with lupus nephritis, the prognosis is good if the glomerular filtration rate is >60 ml/min, proteinuria is lower than 1 g/day and the blood pressure is under control. However, the presence of renal insufficiency, arterial hypertension and antiphospholipid antibodies can increase the risk of lupus flares, hypertension or preeclampsia. The fetal risk has been progressively reduced, although it is still higher in pregnancies of lupus women than in pregnancies of healthy women. Use of immunosuppressive agents during pregnancy is an issue that needs to be considered. Immunosuppression is needed to prevent flares of activity, but questions remain about the safety and long-term mutagenic effects of some drugs.

Glucocorticoids represent the cornerstone of treatment in systemic lupus erythematosus and should be continued in pregnant women without changing their doses. Glucocorticoids may predispose to hypertension and preeclampsia when used at a high dosage, but they may also cause a transient improvement in the manifestations of preeclampsia. There has been concern about a possible relationship between use of glucocorticoids in the first trimester and development of oral clefts [1]. In a prevalence study of 1449 women in Denmark who used glucocorticoids from 30 days before conception throughout the first trimester, oral cleft in the offspring was recorded for only 0.08% of the users, a prevalence lower than the rate of 0.2% observed in the newborns from >80,000 non-users [2]. However, this report had the following limitations: in most cases, inhaled glucocorticoids were used and in only around 200 women, steroids were administered orally; the dosage of oral glucocorticoids was not defined; only one oral cleft was identified in the study group; and the sample size would allow for detection only if the risk was increased >3.5-times. The causes of orofacial clefts are complex, involving both genetic and environmental factors. At present, a possible role of glucocorticoids when used during pregnancy cannot be completely excluded. A small reduction of size at birth may also occur, depending in part on the doses and type of glucocorticoid. Maternal steroids are metabolized by the placental isoenzyme, 11-β-hydroxysteroid dehydrogenase 2. Only inert products of prednisone and analogs cross the placenta [3]. Instead, dexamethasone and betamethasone are less metabolized and may cross the placenta without losing their efficacy, thus favoring low birth weight [4]. When used at low doses, glucocorticoids (<20 mg prednisone daily) are safe for the mother and newborn. At any rate, immunosuppressive therapy with prednisone and analogs should not prevent dexamethasone or betamethasone administration for fetal lung maturation in case of threatened preterm labor.

Cyclophosphamide can cause chromosomal damage, depending on the dosage and duration of therapy. Teratogenicity of cyclophosphamide has been demonstrated in animals, but it is still doubtful in clinical studies. However, cases of malformations have been described when mothers received cyclophosphamide in the first trimester, and miscarriages or preterm deliveries were more frequent in mothers treated with cyclophosphamide [5]. Fetal exposure to cyclophosphamide can induce testicular cancer and gonadal toxicity in mice [6]. Little is known about the long-term risk of cancer or infertility in individuals who were exposed to cyclophosphamide in utero. Thus, cyclophosphamide should not be prescribed during the first trimester of pregnancy. Its use in the second or third trimester should be limited to cases of flares refractory to methylprednisolone pulses or other drugs.

Azathioprine is frequently used in lupus pregnancy. A multicenter study found no difference in the fetal malformation rate between pregnancies exposed to azathioprine and unexposed pregnancies, but there was an association of azathioprine with lower birth weight, gestational age and prematurity [7]. Leukopenia and/or thrombocytopenia may occur in a proportion of neonates whose mothers took azathioprine throughout their pregnancies. According to the available information, there is no evidence that azathioprine use is associated with congenital malformations, spontaneous abortions or stillbirth, but the number of reported cases might not be sufficient to detect a small increase in these defects. The long-term consequences of in utero exposure to azathioprine are largely unknown.

Mycophenolate salts may be teratogenic. It is classified under category D, with a positive evidence of risk, by the US FDA. The European Teratology Information Services reported that the probability of spontaneous abortion in women who received mycophenolate was about 45%. Prematurity (62%) and low birth weight (31%) were frequent. Six out of 29 (20.6%) liveborn infants had major congenital defects [8]. Although maternal disease and concomitant medication may have contributed to these defects, based on these data, the use of mycophenolate in pregnancy should be contraindicated. Given the cumulative effect of mycophenolate, contraceptive measures should be continued for at least 6 weeks after discontinuing the drug. If pregnancy occurs, mycophenolate should be stopped and replaced by azathioprine.

Calcineurin inhibitors are routinely used in transplanted pregnant women. The National Transplantation Pregnancy Registry reported a prevalence of major structural malformations between 4 and 5% in newborns from transplanted mothers mostly treated with cyclosporine or tacrolimus versus 3% in newborns from mothers without diseases [9]. Meta-analysis studies in rheumatic patients could not demonstrate any significant difference in birth defects between pregnancies with prenatal exposure to cyclosporine and controls [10]. Thus, cyclosporine does not appear to be a major human teratogen. However, it may favor the development of hypertension and preeclampsia in pregnant women. Reports on the use of tacrolimus in pregnant women with systemic lupus erythematosus are limited. In newborns from transplant recipients, the risk of major malformations with tacrolimus was low, similar to that of cyclosporine [11]. The pattern of defects is so variable that it is difficult to define. Studies in rabbits showed that in utero exposure to cyclosporine induced nephron reduction, hypertension and chronic renal insufficiency in adulthood [12]. However, pediatric studies did not report deleterious adverse effect of in utero exposure to cyclosporine [13]. Renal function and blood pressure in these children were normal. Due to the limited experience with adolescents and adults, however, a long-term clinical survey is recommended in individuals who were born to mothers treated with calcineurin inhibitors during pregnancy.

Hydroxychloroquine is not a teratogenic drug [14]. A multinational study even showed that hydroxychloroquine may significantly reduce the risk of cardiac-neonatal lupus in pregnant carriers of anti-SSA/Ro-antibody [15]. Since the interruption of hydroxychloroquine may exacerbate the risk of flares, it is recommended to continue the drug in pregnant women with lupus.

Leflunomide demonstrated teratogenic and fetotoxic effects in animals. Thus, leflunomide was formerly contraindicated in pregnant women [16]. However, a prompt washout with cholestyramine or charcoal may reduce the risk of fetal toxicity. In a review of 43 women who were taking leflunomide during pregnancy or prior to conception and used a washout procedure after counseling, pregnancy resulted in liveborn infants in 93% of cases. There were two infants with major malformations from 16 mothers who were exposed during pregnancy, and no malformations were reported in the preconception group [17]. Since leflunomide metabolites are detectable in plasma for a long period, pregnancy should be programmed at least 2 years after discontinuation of the drug. On the other hand, women who inadvertently become pregnant while taking leflunomide may have chances of a fair outcome if they promptly adopt an adequate washout procedure.

Methotrexate is teratogenic drug. Its use in the first trimester of pregnancy can cause growth retardation and a number of fetal malformations due to the absence of frontal bones and the skeletal abnormalities to micrognathia [18].

There is little data about the use of monoclonal antibodies. Rituximab undergoes very low transplacental maternofetal transfer during the first trimester of pregnancy. Anecdotal data reported safe pregnancies and deliveries in patients who received rituximab in the first trimester [19]. When given in the second or third trimester, rituximab can cross the placenta and cause lymphopenia in the newborn. Thus, live vaccines should be avoided in children with in utero exposure to rituximab for at least the first 6 months of life.

Belimumab pregnancy registry reported only two outcomes. One patient, exposed to belimumab 6 weeks preconception, delivered a liveborn neonate at 35 weeks of gestation by cesarean delivery after uterine contractions with no cervical dilation. The second patient delivered a liveborn neonate at 32-5/7 weeks of gestation after placental abruption. No birth defects were reported [20]. In summary, the available data are insufficient to evaluate the risk associated with the use of rituximab in pregnancy, and such therapy in pregnant patients should be administered only in selected situations with adequate counseling to the mother.

On the basis of the available knowledge, we recommend the following guidelines to maximize the chances of successful pregnancy in women with systemic lupus erythematosus.

• Pregnancy should be delayed until lupus is quiescent. Such a policy can allow to minimize the risk of flares, to use low doses of immunosuppressive drugs and to reduce the maternal risks during pregnancy.

• Treatment should be preferentially based on glucocorticoids alone or associated with azathioprine. Glucocorticoids at low doses are generally well tolerated. Although azathioprine may have teratogenic effects in animals, clinical studies did not show an excess of malformation in women exposed to the drug during pregnancy.

• The dosage of glucocorticoids and azathioprine in stable patients should be neither increased nor reduced.

• To reduce the risk of fetal toxicity, mycophenolate salts and leflunomide should be discontinued some weeks before conception and cyclophosphamide should be withdrawn before conception. These drugs may be safely replaced by azathioprine in patients with inactive lupus. Since little information is available about the safety of monoclonal antibodies in pregnant women, we suggest not to use them in pregnant women.

• In case of arthralgias, rash or asthenia, hydroxychloroquine may be introduced or prednisone doses may be slowly increased. In case of severe flares, a short course of intravenous methylprednisolone pulses is suggested (250–500 mg each according to the body weight and severity of flares). If steroid pulses are insufficient, cyclosporine or tacrolimus can be introduced and the doses of oral prednisone can be increased.

Lactation

Prednisone at doses lower than 20 mg/day and hydroxychloroquine are found in low levels in milk and would not be expected to cause any adverse effects in breastfed infants. There are conflicting views about the safety of nursing in mothers taking immunosuppressive drugs such as azathioprine, cyclosporine and cyclophosphamide. With the exception of cases of mild asymptomatic neutropenia, no short-term adverse effects have been reported in infants exposed to azathioprine during breastfeeding. Similarly, children exposed to cyclosporine during breastfeeding were healthy with normal kidney function. Cases of neutropenia have been reported in children exposed to cyclophosphamide during lactation. However, long-term follow-up to study the carcinogenic effects of these drugs has not been performed. This issue has been poorly addressed in the literature.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.