Review
Safety considerations when prescribing immunosuppression medication to pregnant women 1.
Introduction
2.
Drugs allowed during pregnancy
3.
Drugs contraindicated during
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pregnancy 4.
Conclusion
5.
Expert opinion
Maria Gerosa†, Pier Luigi Meroni & Rolando Cimaz †
University of Milan, Ospedale Gaetano Pini, Division of Rheumatology, Department of Clinical Sciences and Community Health, Milan, Italy
Introduction: In the past two decades, the number of women with autoimmune and inflammatory diseases experiencing a pregnancy has significantly increased in parallel with the enormous advances in the diagnosis and management of these disorders. However, information regarding the safety of immunosuppressive agents comes from case reports and case series and no controlled trials are available. Areas covered: We performed a review of the literature using MEDLINE. The term ‘pregnancy’ was searched in combination with all the principal immunomodulant/immunosuppressive drugs used in rheumatic diseases. Expert opinion: A large number of reports suggest that azathioprine, cyclosporine, hydroxychloroquine and steroids are relatively safe during pregnancy, whereas methotrexate, cyclophosphamide, mycophenolate mofetil and leflunomide are contraindicated. Data about the safety of biological agents are scant, but a growing number of publications suggest that at least TNF inhibitors could be prescribed when benefits outweigh the potential risks. Nevertheless, we cannot draw definite conclusions, as this information has not been confirmed in controlled trials. Prospective registries, some of which are already in place, are invaluable resources to answer many questions, especially on the incidence of fetal malformations. Finally, outcome studies on the offspring especially in regard to immune system and psychomotor development will shed light on long-term safety. Keywords: azathioprine, biological agents, cyclosporine, immunosuppressive drugs, leflunomide, methotrexate, mycophenolate mofetil, pregnancy, steroids, TNF inhibitors Expert Opin. Drug Saf. [Early Online]
1.
Introduction
In the past two decades, the number of women suffering from autoimmune and/or inflammatory diseases experiencing one or more pregnancies has significantly increased in parallel with the enormous advances in the diagnosis and management of these disorders and the better knowledge of their pathogenesis. Women affected by rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SSc), Sj€ogren’s syndrome or other systemic inflammatory conditions usually need chronic treatment with immunomodulant or immunosuppressive agents, and the safety of such drugs during pregnancy represents a major concern for both the clinicians and the patients. Information regarding the safety of immunosuppressive drugs during pregnancy is scant, as therapeutic trials exclude pregnant women. The few data available are derived from case reports or case series. In addition to teratogenicity, an important issue that should be taken into consideration for the assessment of safety of this class of drugs concerns potential effects on the development of the immune system of the fetus. Moreover, the need to stop a 10.1517/14740338.2014.951326 © 2014 Informa UK, Ltd. ISSN 1474-0338, e-ISSN 1744-764X All rights reserved: reproduction in whole or in part not permitted
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M. Gerosa et al.
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The proportion of women suffering from autoimmune and/or inflammatory diseases who experience one or more pregnancies has significantly increased in the past two decades. A tight control of autoimmune/inflammatory diseases such as rheumatoid arthritis, systemic lupus erythematosus or inflammatory bowel diseases is important to improve pregnancy outcome in these patients. At present, methotrexate, cyclophosphamide, mycophenolate mofetil and leflunomide are absolutely contraindicated during pregnancy. Azathioprine, cyclosporine, hydroxychloroquine and steroids can be prescribed during pregnancy, if the benefits from treatment outweigh the potential risks. Further data are needed to assess the real safety of biological agents, but maybe TNF inhibitors could be allowed in selected patients with a very severe flare of disease, during the first and second trimester.
This box summarizes key points contained in the article.
potentially harmful treatment at the beginning of pregnancy has to be weighed against the risk of relapse of disease associated with discontinuation. In fact, disease activity at conception and during gestation can strongly affect pregnancy outcome. In SLE patients, the risk of fetal loss in women with active lupus nephritis has been reported to range from 8 to 36%, and active renal involvement or other forms of increased lupus activity in the first and second trimester have been associated with a higher incidence of preterm birth, intrauterine growth restriction (IUGR) and preeclampsia [1]. Relapses of RA or SSc are associated with a lesser risk of adverse pregnancy outcome in comparison to SLE; nevertheless, an active disease has been associated with higher incidence of prematurity and IUGR in these disorders as well [2,3]. Thus, treatment decision-making in women with systemic autoimmune or inflammatory diseases willing to have a baby or who become inadvertently pregnant should evaluate all these aspects. In fact, a very large number of publications suggest that some immunosuppressive drugs, for example, thiopurines or cyclosporine, are relatively safe during pregnancy. On the other hand, several authors report that an active disease during pregnancy may represent a risk factor for congenital abnormalities by itself. Pregnancy in rheumatic patients should be carefully planned and treatment should be chosen in order to achieve the better disease control, together with the lowest risks for the fetus. These patients should be recommended to conceive during a period of longstanding remission, in order to minimize the risks of flare and subsequent adverse pregnancy outcome. Women with autoimmune or inflammatory diseases of childbearing age should undergo multidisciplinary preconceptional counseling for the evaluation of all these aspects. 2
The FDA has created a classification system to define the risk of drug teratogenicity. This classification includes five categories (A, B, C, D and X), considering both the potential risks of and benefits from the drug, with data largely based on animal studies [4]. 2.
Drugs allowed during pregnancy
Glucocorticoids Glucocorticoids (GCs) are the most widely used medications in rheumatic diseases, alone or in combination with other disease-modifying drugs. Non-fluorinated steroids, such as prednisone and prednisolone, commonly used in managing SLE and RA flares, cross the placenta in very low concentrations, whereas fluorinated steroids (betamethasone and dexamethasone) are able to reach the fetal circulation in higher amounts [5]. Studies on animal models have demonstrated that GCs are teratogens in rodents and the oldest studies of antenatal exposure during the first trimester reported an increased incidence of orofacial cleft in humans [6,7]. Nevertheless, data from the literature are not univocal, as several authors reported a 1.7to 3.4-fold increased risk of developing palatal cleft after in utero GC exposure, whereas other studies did not confirm these findings [8-10]. Recently, a Danish population-based study, including > 50,000 exposed pregnancies, did not identify any significant increased risk of orofacial cleft associated with GC use, irrespective of the type of administration [11]. Even if this study adds further evidence of the safety of these molecules, these data should be carefully evaluated. Data about the timing of the use of steroids during pregnancy and the pregnancy outcomes were in fact inferred based on registry data, without personal verification, possibly overestimating the number of women really taking the medication during the first trimester. Taken together, all literature data suggest that GC use during pregnancy is associated with a mild increase of the possibility of orofacial cleft, with an estimated risk of about 1 in 300 live births. In addition to embryotoxicity, several other adverse effects have been associated with steroids during pregnancy. Their administration during the third trimester increases the chance of gestational hypertension and diabetes, osteoporosis, IUGR and preterm delivery due to premature membrane rupture [12]. Moreover, based on studies on animal models suggesting a relationship between prenatal exposure to GCs and altered offspring brain development, several authors have attempted to assess a similar effect in humans [13,14]. A recent study on a large, longitudinal cohort of children prospectively followed up until 16 years of age demonstrated that a single prenatal administration of fluorinated GCs was significantly associated with general psychological disturbances and attention deficit in childhood, after adjustment for relevant confounders [15]. However, neurodevelopment is subject to multiple environmental factors and a true causal relationship in this setting is very hard to assess. 2.1
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Safety considerations when prescribing immunosuppression medication to pregnant women
In rheumatic patients, chronic GC use is associated with reduced bone mineral density (BMD), raising the hypothesis that their use during pregnancy could influence the BMD of the offspring. However, a recent study has evaluated the BMD of 108 children of RA patients and found that prednisone use during pregnancy was not associated with low BMD [16]. In a cohort of women with connective tissue diseases, we have obtained similar results (unpublished data). Antimalarials Antimalarials are widely used for the treatment of rheumatic diseases. Although data from animal models and the first experiments on humans suggested a potential eye and ear toxicity, several further case series demonstrated that chloroquine and hydroxychloroquine (HCQ) are safe and should not be discontinued during pregnancy [17]. Actually, HCQ has been demonstrated to have pleiotropic effects in lupus patients that could be especially noteworthy during pregnancy [18]. HCQ reduces lipid levels and the risk of thromboembolic events in SLE and reduces the risk of lupus flares [18]. Clowse et al. report that discontinuation of HCQ prior to conception is associated with an increased risk of SLE flares [17]. Moreover, it has been recently suggested that prenatal exposure to HCQ decreases the risk of congenital heart block in children of anti-SSA/Ro-positive mothers [19].
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2.2
Azathioprine and cyclosporine Azathioprine and cyclosporine represent the two most common therapeutic options for immunosuppression during pregnancy in rheumatic patients [20]. Their safety has been widely confirmed by the experience in solid organ transplanted women. Initially, large transplant registries had shown that the use of azathioprine during pregnancy was not associated with an increased risk of congenital anomalies [21,22]. Reassuring information are also derived from studies in inflammatory bowel diseases (IBDs). A very large recent meta-analysis demonstrated that azathioprine use during pregnancy was not associated with an increased risk of birth defects, even if there was slightly increased risk of preterm delivery (odds ratio [OR] = 1.67; 95% CI: 1.26, 2.20) in the treated group [23]. More recently, a study on a large population of IBD patients showed a very low rate of major congenital anomalies in children of patients treated with azathioprine, which accounted for an adjusted OR of a major congenital anomaly associated with drug use of 1.27 [24]. Immunosuppression of cyclosporine is mediated by inhibition of lymphocyte proliferation and downregulation of T-helper cell function that leads to decreased secretion of proinflammatory cytokines. As its first indication was prevention of transplant rejection, most of literature data address its safety during pregnancy in women who underwent organ transplantation. Cyclosporine is highly lipophilic and crosses the placenta in great amounts. Nevertheless, a large number of publications including > 5000 pregnancies in transplanted 2.3
women treated with cyclosporine did not show a substantial teratogenic effect. However, a high rate of preeclampsia, preterm delivery and low birth weight in infants has been described. These pregnancy complications were more frequent in kidney- and heart-transplanted women, in comparison to liver and lung transplantations, suggesting a significant effect of the underlying disease and/or preexisting maternal comorbidities [25]. The literature considering cyclosporine safety during pregnancy in autoimmune patients is limited to case reports or case series accounting for about 50 pregnancies. No increased risk of fetal anomalies have been described in these populations, even if again there was a higher incidence of low birth weight and prematurity in comparison to what is expected in the general population (although lower than what is observed in transplanted patients) [20,25]. Studies addressing the potential influence of cyclosporine on the fetal immune system did not show a significant immunosuppressive effect of the drug [26,27]. Cyclosporine is classified in the pregnancy risk category C by the FDA. 3.
Drugs contraindicated during pregnancy
Methotrexate Methotrexate has antiproliferative activity and inhibits DNA synthesis through the inhibition of dihydrofolate reductase [28]. In studies on animal models, the administration of methotrexate during pregnancy was associated with embryolethality in rats and monkeys, whereas an embryotoxic effect was more common in mice and rabbits [28]. In humans, a typical embryopathy, mainly characterized by pulmonary atresia, craniosynostosis and limb deficiencies, had been initially hypothesized with methotrexate exposure [29], and recently confirmed in an exhaustive teratogen update [28]. The sensitive period for the induction of these embryo abnormalities has been recognized between the 6th and the 8th weeks after conception, and the critical levels of maternal drug was suggested to be ‡ 10 mg/week [28]. However, a case of typical methotrexate embryopathy has been very recently described in one of eight pregnancies exposed to a lower dose (7.5 mg weekly) [29]. More recently, a distinct syndrome, including tetralogy of Fallot and possibly neural crest anomalies, has been described for very early (4th week of gestation) high-dose methotrexate treatment for ectopic pregnancy misdiagnosis [30-32]. In 2014, two different studies reporting conflicting results have been published regarding the outcome of methotrexateexposed pregnancies in rheumatic diseases. Cooper et al. [33], in an observational study using claims data from three US health plans, have identified a total of 608 pregnancies in immune-mediated diseases, including 23 patients taking methotrexate during the first trimester of pregnancy. In the methotrexate group, there were no statistical differences regarding the rate of congenital malformations in comparison to pregnancies taking other immunosuppressive medications (TNF inhibitors [TNFi], HCQ, azathioprine, gold, 3.1
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M. Gerosa et al.
sulfasalazine and leflunomide) or patients not exposed to immunosuppression (4.3 vs 2.3% in non-treated women), with a propensity score-adjusted risk ratio (RR) of 1.42. However, fetal deaths occurred most frequently among patients treated with methotrexate (8.7 vs 2.3% in nontreated women), with a RR of 3.18 [33]. Discordant results have been reported by Weber-Schoendorfer et al. [34] in a prospective multicenter cohort study, including 188 pregnancies exposed to methotrexate (median weekly dosage of 10 mg/week, higher weekly dosage of 30 mg/week) after conception and 136 patients who had stopped the drug within 12 weeks before conception. The cumulative incidence of spontaneous abortion in the post-conception exposed cohort was significantly higher than that observed in those who stopped the drug before conception and also in 459 disease-matched non-exposed patients and 1107 non-autoimmune women (42.5 vs 14,4%, 22.5 and 17.3%, respectively). Moreover, there was a significant increase in the rate of birth defects (6.6%) in the methotrexate postconception group in comparison to the non-autoimmune disease cohort (2.9%), whereas the rate of birth defects in the pre-conception treated group and the disease-matched group was lower (3.5 and 3.6%) but not significantly different [34]. In conclusion, even if some recent studies report a lower rate of congenital abnormalities in infants born to mothers exposed to low-dose methotrexate during pregnancy, the drug has to be still considered embryotoxic and should be discontinued at least 12 weeks before conception, as the whole data available in the literature do not suggest that possible benefit outweigh the potential risks (category X of the FDA) [35]. Leflunomide When leflunomide was approved for the treatment of RA, there were major concerns regarding its embryotoxic potential, as it was demonstrated to be highly teratogenic in rats, rabbits and mice [36]. Consequently, it was included in the FDA category X and absolutely contraindicated during pregnancy. Moreover, due to its very long half-life, patients who were planning a pregnancy were advised to discontinue the drug at least 2 years before, and a washout procedure with cholestyramine for 12 days was recommended in case of unintended pregnancy. Given these strong warnings to prevent unintended exposure, data regarding the effect of leflunomide in humans are poor. The first report described the occurrence of severe prematurity, cerebral palsy and unilateral blindness in an infant exposed to leflunomide in utero. However, subsequent studies reported no malformations in 14 exposed pregnancy. Recently, the Organization of Teratology Information Specialists collaborative research group published two prospective, controlled cohort studies comparing the incidence of fetal anomalies in exposed and non-exposed pregnancies in RA patients. Although the authors concluded that leflunomide 3.2
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exposure did not increase the risk of adverse pregnancy outcome in RA patients after adjustment for confounders, the two studies showed that the rate of major malformations in patients who received at least one dose of leflunomide after conception was 6.9%, which is higher than what was observed in healthy pregnancies [37,38]. Moreover, most of these patients received one or more cholestyramine washout procedures, potentially reducing the risk of its transplacental passage [20,37]. In conclusion, even if this recent data suggest that leflunomide could not be a potent teratogen, the literature is still controversial and washout procedures before conception or in case of unintended pregnancy are recommended [20]. Cyclophosphamide Cyclophosphamide is an alkylating cytotoxic agent that is used for the treatment of hematological malignancies and a variety of solid tumors, but it is also extensively used in the management of severe lupus flares, vasculitis and other connective tissue diseases. It is able to induce ovarian failure depending on the age of the patients and the cumulative dose [39]. Moreover, it has been widely demonstrated to be embryotoxic and teratogen both in animals and humans. There are some case reports of the use of this drug during the second and third trimester without development of malformations, whereas the embryo exposure during the first weeks of gestation has been associated with a high rate of congenital abnormalities that has been included in a characteristic embryopathy by some authors [12,20]. 3.3
Mycophenolate mofetil Mycophenolate mofetil (MMF) is an inhibitor of inosine monophosphate dehydrogenase that exerts its antimetabolite effects via the inhibition of purine synthesis [40]. The drug has been originally approved for the prevention of transplant rejection, but more recently, due to its potent effects on Tand B-lymphocyte proliferation, it has been successfully used in the treatment of autoimmune diseases [40]. MMF has been initially classified as pregnancy category C by the FDA, but several reports of embryo toxicity have led to the reclassification of the drug in category D [41]. Unintended exposure to MMF during pregnancy has been associated with a significant increased risk of miscarriages and also of fetal anomalies [42-45]. Specifically, a typical pattern of abnormalities, including craniofacial malformations, abnormality of distal limbs and heart and esophagus or renal defects, have led to the definition of a characteristic mycophenolate embryopathy [43,44]. In a very recent prospective study evaluating pregnancy outcome in a cohort of liver and cardiothoracic transplant recipients, MMF was significantly associated (OR = 5.3) with poor fetal outcome [45]. In September 2012, the FDA approved a risk evaluation and mitigation strategy (REMS) system to evaluate if the benefits of MMF outweigh the risks [41]. REMS is a process with the aim to mitigate the risk related to a specific drug. The primary objective of REMS is to assess and manage recognized or potential 3.4
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Safety considerations when prescribing immunosuppression medication to pregnant women
significant medication-related risks and to ensure continual pharmacovigilance [46]. Biological agents Biologics are the most recent drugs that have been brought onto the market for the treatment of rheumatic diseases. Due to their relatively recent availability, data regarding their safety during pregnancy are generally poor except for TNFi. The majority of biological agents contain the fragment crystallizable region (Fc) of IgG that is supposed to mediate the active transport of these drugs through the placenta in the fetal circulation, starting from the second trimester [47]. In this regard, Mahadevan et al. have recently demonstrated that levels of infliximab and adalimumab in the blood of neonates that were antenatally exposed to these drugs were comparable or higher than maternal levels at term [47]. In the same study, concentrations of certolizumab pegol, a TNFi that does not contain the Fc fragment, were not detectable in the infant circulation [47]. First data regarding the safety of TNFi were not reassuring, as one study reported a high incidence of congenital abnormalities of the vertebral anomalies, anal atresia, cardiac defects, tracheoesophageal fistula and/or esophageal atresia, renal and radial anomalies and limb (VACTERL) defects spectrum in infants accidentally exposed antenatally to infliximab and etanercept [47]. However, this report should be carefully evaluated because only 1 of the 41 reported abnormalities was consistent with the definition of VACTERL [48]. Accordingly, subsequent data did not confirm these findings, and no further report of VACTERL association abnormalities have been described in TNFi-exposed infants up to now. On the contrary, there is a growing body of evidence that TNFi use during pregnancy is not associated with adverse pregnancy outcomes or congenital malformations [49,50]. A recent systematic review of the literature on 58 publications, including > 1500 pregnancies in IBD patients, has shown that the rate of adverse pregnancy outcome and malformation in treated women is not significantly higher than what is expected in the general population [4]. However, the use of these drugs during the third trimester could interfere with the physiological development of the immune system of the fetus, increasing the risk of neonatal infections [51]. The experiments with the other available biological agents are very limited, mostly related to reports on rituximab use both in lymphoproliferative and in rheumatic diseases. Chakravarty et al. [52] reviewed a total of 153 published cases with a known outcome, reporting 22% of miscarriages, 24% of preterm deliveries and 2.2% of congenital malformations. This review raised a major concern about the effect of antiCD20 therapy on the neonatal immune system, as 4 babies developed severe infections soon after birth and 11 others displayed hematological abnormalities [52]. Since 2011, three additional case reports of women receiving rituximab at the beginning or just before pregnancy have been published [53,54]: two healthy babies and one mildly small for gestational age were the results of these deliveries.
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3.5
Published reports of unintended in utero exposure to abatacept included 10 pregnancies occurring during the open-label phase of a trial on RA and multiple sclerosis [51]. Four ended in spontaneous abortions, three ended in elective terminations and no data are available for the other three. Another report described the successful pregnancy of a woman affected by RA [53]. Current available data on the safety of tocilizumab during pregnancy are scant and have been published so far only in abstract form. Rubbert-Roth et al. reported on 32 pregnancies in RA patients receiving tocilizumab. Thirteen of these patients choose an elective termination and seven experienced a spontaneous abortion. Of the 11 babies, 10 were born at term without pregnancy complications, 1 died of acute respiratory distress syndrome, 3 days after an emergency delivery for obstetrical complications [55]. Belimumab received regulatory approval for the treatment of SLE only in 2011; therefore, very few information is available about its use during pregnancy. GlaxoSmithKline has reported that 83 pregnancies have occurred during placebo-controlled Phase II and Phase III studies. Of these, 27.7% had spontaneous abortions and 24% had an elective termination. Three congenital anomalies occurred in this population (3.6%), but one was associated with a chromosomal translocation that was also found in the mother, and thus was considered to be unrelated to belimumab [18]. The manufacturer has created an online pregnancy registry for the evaluation of pregnancy and infant outcomes in women with SLE exposed to commercially supplied belimumab during pregnancy or in the preceding 4 months. The registry reports that up to now six out of seven pregnancies that occurred during belimumab therapy ended with the birth of healthy babies, even if half of them were preterm. In addition, one of the preterm infants displayed an Ebstein’s anomaly of the cardiac tricuspid valve, a mild congenital heart defect [56]. 4.
Conclusion
With improvements in clinical care, more data on safety of immunosuppressive and antirheumatic treatments during pregnancies have accumulated (Table 1). Several of these drugs, once considered contraindicated during pregnancy, have now been shown to be relatively safe. However, many questions, especially those related to the long-term outcomes in the offspring, are still unanswered. In regard to the new (biologic) drugs, the use of TNFi seems to be relatively safe, even if their use has to be carefully balanced against potential known and yet unknown risks. Considering other biotherapies, they have generally not been used long enough to precisely assess their safety during pregnancy, since the numbers are still small. Different registries are in place in order to evaluate potential side effects (e.g., teratogenicity) and the rarity of these situations make these tools fundamental in order to have reliable answers on frequencies and relative risks of complications.
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6
No increase in malformations [17] No increase in malformations [21-24] No increase in malformations [20,25] Typical embryopathyz [28,29] Tetralogy of Fallot and possibly neural crest anomalies [30-32] Inconstant report of increased rate of congenital malformations [36-38] Increased rate of congenital malformations [12,39]
Antimalarials
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C X
Low birth weight [25] Cytopenia [28]
Preeclampsia, preterm delivery [25] Abortion, fetal death [33,34]
Miscarriage and prematurity uncertain [52] Miscarriage [51] Miscarriage Spontaneous abortion [18,56]
Not reported
Possible effects on immune system, development of mild increased risk of neonatal infections, no vaccinations during the first 6 months of life [49,51] B-cell depletion, with risk of infections [52] Insufficient available data Insufficient available data Insufficient available data
IUGR, cytopenia, impaired neurological development [12,39] Not reported
Not reported
Not reported
Not reported
Not reported
C C C
C
B
D
D
X
D
C
None
None Preterm delivery [23]
Prednisone B others C
FDA category
IUGR [12], psychological disturbances* [13-15] None
Effects on fetus/infant
Hypertension, diabetes, osteoporosis, PPROM [12]
Pregnancy outcome
*With fluorinated glucocorticoids. z Pulmonary atresia, craniosynostosis and limb abnormalities. § Very few information available about use during pregnancy. IUGR: Intrauterine growth restriction; PPROM: Preterm premature rupture of membrane.
Abatacept§ Tocilizumab§ Belimumab§
Insufficient available data Insufficient available data [55] Increased risk of malformation [18,56]
Insufficient available data
Rituximab
TNF inhibitors
Craniofacial malformations, abnormality of distal limbs and heart and esophagus or renal defects [41-45] No increase in malformations [4,47,49,50]
Mycophenolate mofetil
Cyclophosphamide
Leflunomide
Methotrexate
Cyclosporine
Azathioprine
Mild risk (1/300) of orofacial cleft [8-11]
Teratogenicity
Glucocorticoids
Drug
12 weeks before conception 12 weeks before conception 12 weeks before conception
6 months before
At conception
12 weeks before conception
2 years before conception, washout procedure with cholestyramine recommended 6 months before conception
12 weeks before conception
No
No
No
No
Discontinuation
Table 1. Embryotoxicity and effects on pregnancy outcome and fetus/infant development of glucocorticoids, immunomodulant and immunosuppressive drugs.
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M. Gerosa et al.
Safety considerations when prescribing immunosuppression medication to pregnant women
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5.
Expert opinion
Information regarding the effects of immunosuppressive drugs on the process of embryogenesis and fetal development are lacking, as therapeutic trials usually exclude pregnant women. The few data available usually derive from case reports of inadvertent drug exposure during unplanned pregnancies. Nevertheless, with time it has been possible to collect more safety data, and several of these drugs such as HCQ, cyclosporine, azathioprine and corticosteroids have been demonstrated not to have relevant effects on embryogenesis and are now allowed during pregnancy. On the contrary, contrasting data are available in the literature regarding other immunosuppressants such as methotrexate, leflunomide and TNFi, as some authors have reported a teratogenic effect of these drugs, whereas other studies do not confirm these findings. The weaknesses of the research mainly depend on the type of studies, since we cannot draw firm conclusion from case reports and case series only. As randomized controlled trials are not feasible due to ethical issues, the collection of data from large-scale, population-based cohorts of women with systemic inflammatory diseases could be a valid alternative for safety assessment. Moreover, we think that prospective registries, some of which are already in place in different parts of the world, are Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.
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Declaration of interest 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. risk of orofacial clefts. CMAJ 2011;183:796-804
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Paziana K, Del Monaco M, Cardonick E, et al. Cyclosporin use during pregnancy. Drug Saf 2013;36:279-29
26.
Cimaz R, Meregalli E, Biggioggero M, et al. Alterations in the immune system of children from mothers treated with immunosuppressive agents during pregnancy. Toxicol Lett 2004;149:155-62
27.
Peart E, Clowse MEB. Systemic lupus erythematosus and pregnancy outcomes: an update and review of the literature. Curr Opin Rheumatol 2014;26:118-23 Izmirly PM, Saxena A, Kim MY, et al. Maternal and fetal factors associated with mortality and morbidity in a multiracial/etnic registry of anti-SSA/Roassociated cardiac neonatal lupus. Circulation 2011;124:1927-35 Congenital heart block is a very severe complication and no effective pharmacological treatment is currently available. The demonstration of a potential effect of hydroxychloroquine could be extremely important for its prevention.
Akbari M, Shah S, Velayos FS, et al. Systematic review and meta-analysis on the effects of thiopurines on birth outcomes from female and male patients with inflammatory bowel disease. Inflamm Bowel Dis 2013;19:15-22 This systematic review includes a very large cohort of patients and further confirms the safety of azathioprine during pregnancy. Ban L, Tata LJ, Fiaschi L, Card T. Limited risks of major congenital anomalies in children of mothers with
cohort study. Arthritis Rheumatol 2014;66:1101-10
IBD and effects of medications. Gastroenterology 2014;146:76-84
28.
..
29.
Biggioggero M, Borghi MO, Gerosa M, et al. Immune function in children born to mothers with autoimmune diseases and exposed in utero to immunosuppressants. Lupus 2007;16:651-6 Hyoun SC, Obicˇan SG, Scialli AR. Teratogen update: methotrexate. Birth Defects Res A Clin Mol Teratol 2012;94:187-207 This is a recent updated review of potential teratogen effects of methotrexate. Feldkamp M, Carey JC. Clinical teratology counseling and consultation case report: low dose methotrexate exposure in the early weeks of pregnancy. Teratology 1993;47:533-9
30.
Martı´n MC, Barbero P, Groisman B, et al. Methotrexate embryopathy after exposure to low weekly doses in early pregnancy. Reprod Toxicol 2014;43:26-9
31.
Nurmohamed L, Moretti ME, Schechter T, et al. Outcome following high-dose methotrexate in pregnancies misdiagnosed as ectopic. Am J Obstet Gynecol 2011;205:533
32.
Poggi SH, Ghidini A. Importance of timing of gestational exposure to methotrexate for its teratogenic effects when used in setting of misdiagnosis of ectopic pregnancy. Fertil Steril 2011;96:669-71
33.
34.
Cooper WO, Cheetham TC, Li DK, et al. Risk of adverse fetal outcomes associated with immunosuppressive medications for chronic immunemediated diseases and pregnancy. Arthritis Rheumatol 2014;66:444-50 Weber-Schoendorfer C, Chambers C, Wacker E, et al. Pregnancy outcome after methotrexate treatment for rheumatic disease prior to or during early pregnancy: a prospective multicenter
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35.
Kim SC, Hernandez-Diaz S. Safety of immunosuppressive drugs in pregnant women with systemic inflammatory diseases. Arthritis Rheumatol 2014;66:246-9
36.
Brent RL. Teratogen update: reproductive risks of leflunomide (Arava); a pyrimidine synthesis inhibitor: counseling women taking leflunomide before or during pregnancy and men taking leflunomide who are contemplating fathering a child. Teratology 2001;63:106-12
37.
Chambers CD, Johnson DL, Robinson LK, et al. Birth outcomes in women who have taken leflunomide during pregnancy. Arthritis Rheum 2010;62:1494-503 These two prospective, controlled cohort studies compare the incidence of fetal anomalies in pregnancies exposed or non-exposed to leflunomide and show that the rate of major malformations in patients who received at least one dose of leflunomide after conception is higher than what is observed in healthy pregnancies.
.
38.
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Cassina M, Johnson DL, Robinson LK, et al. Pregnancy outcome in women exposed to leflunomide before or during pregnancy. Arthritis Rheum 2012;64:2085-94 These two prospective, controlled cohort studies compare the incidence of fetal anomalies in pregnancies exposed or non-exposed to leflunomide and show that the rate of major malformations in patients who received at least one dose of leflunomide after conception is higher than what is observed in healthy pregnancies.
39.
Harvard LE, Mithcel K, Piepel C. The impact of cyclophosphamide on menstruation and pregnancy in women with rheumatologic disease. Lupus 2013;22:81-6
40.
Ransom JT. Mechanism of action of mycophenolate mofetil. Ther Drug Monit 1995;17:681-4
41.
Kim M, Rostas S, Gabardi S. Mycophenolate fetal toxicity and risk evaluation and mitigation strategies. Am J Transplant 2013;13:1383-9
42.
Merlob P, Stahl B, Klinger G. Tetrada of the possible mycophenolate mofetil
Safety considerations when prescribing immunosuppression medication to pregnant women
infliximab and adalimumab, but not certolizumab, cross the placenta even if they do not induce a high rate of malformations.
embryopathy: a review. Reprod Toxicol 2009;28:105-8 43.
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Anderka MT, Lin AE, Abuelo DN, et al. Reviewing the evidence for mycophenolate mofetil as a new teratogen: case report and review of the literature. Am J Med Genet A 2009;149A:1241-8 Hoeltzenbein M, Elefant E, Vial T, et al. Teratogenicity of mycophenolate confirmed in a prospective study of the European Network of Teratology Information Services. Am J Med Genet A 2012;158A:588-96
48.
Carter JD, Ladhani A, Ricca LR, et al. A safety assessment of tumor necrosis factor antagonists during pregnancy: a review of the Food and Drug Administration database. J Rheumatol 2009;36:635-41
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Ostensen M, F€orger F. Treatment with biologics of pregnant patients with rheumatic diseases. Curr Opin Rheumatol 2011;23:293-8
Mohamed-Ahmed O, Nelson-Piercy C, Bramham K, et al. Pregnancy outcomes in liver and cardiothoracic transplant recipients: a UK national cohort study. PLoS One 2014;9:e89151 This is a very recent prospective study that confirms the strong teratogenic and embryotoxic effect of mycophenolate mofetil.
50.
Chambers CD, Johnson DL. Emerging data on the use of anti-tumor necrosis factor-alpha medications in pregnancy. Birth Defects Res A Clin Mol Teratol 2012;94:607-11
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Gabardi S. Understanding risk evaluation and mitigation strategies in organ transplantation. Pharmacotherapy 2011;31:714-22
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Mahadevan U, Wolf DC, Dubinsky M, et al. Placental transfer of anti-tumor necrosis factor agents in pregnant patients with inflammatory bowel disease. Clin Gastroenterol Hepatol 2013;11:286-92 This study provides the first in vivo demonstration on humans, that
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Ostensen M. Safety issues of biologics in pregnant patients with rheumatic diseases. Ann N Y Acad Sci 2014;1317:32-8 This is a recent updated review that summarizes the most recent publications reporting on TNF inhibitor’s exposure during pregnancy and confirms that it is not associated with adverse pregnancy outcomes or congenital malformations. Chakravarty EF, Murray ER, Kelman A, Farmer P. Pregnancy outcomes after maternal exposure to rituximab. Blood 2011;117:1499-506
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Ojeda-Uribe M, Afif N, Dahan E, et al. Exposure to abatacept or rituximab in the first trimester of pregnancy in three women with autoimmune diseases. Clin Rheumatol 2013;32:695-700
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Gualtierotti R, Ingegnoli F, Meroni PL. Pre-conceptional exposure to rituximab: comment on the article by OjedaUribe et al. Clin Rheumatol 2013;32:727-8
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Rubbert-Roth A, Goupille PM, Moosavi S, et al. First experiences with pregnancies in RA patients receiving tocilizumab therapy. Arthritis Rheum 2010;62:S161
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Landy H, Powell M, Hill D, et al. Belimumab pregnancy registry: prospective cohort study of pregnancy outcomes. Obstet Gynecol 2014;123(Suppl 1):62S
Affiliation
Maria Gerosa†1 MD, Pier Luigi Meroni1 & Rolando Cimaz2 † Author for correspondence 1 University of Milan, Ospedale Gaetano Pini, Division of Rheumatology, Department of Clinical Sciences and Community Health, via Pini 9, 20122 Milan, Italy Tel: +390258296719; Fax: +390258296315; E-mail: [email protected] 2 Anna Meyer Children’s Hospital and University of Florence, via Pieraccini 24, 50141, Florence, Italy
9
Safety considerations when prescribing immunosuppression medication to pregnant women 1.
Introduction
2.
Drugs allowed during pregnancy
3.
Drugs contraindicated during
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pregnancy 4.
Conclusion
5.
Expert opinion
Maria Gerosa†, Pier Luigi Meroni & Rolando Cimaz †
University of Milan, Ospedale Gaetano Pini, Division of Rheumatology, Department of Clinical Sciences and Community Health, Milan, Italy
Introduction: In the past two decades, the number of women with autoimmune and inflammatory diseases experiencing a pregnancy has significantly increased in parallel with the enormous advances in the diagnosis and management of these disorders. However, information regarding the safety of immunosuppressive agents comes from case reports and case series and no controlled trials are available. Areas covered: We performed a review of the literature using MEDLINE. The term ‘pregnancy’ was searched in combination with all the principal immunomodulant/immunosuppressive drugs used in rheumatic diseases. Expert opinion: A large number of reports suggest that azathioprine, cyclosporine, hydroxychloroquine and steroids are relatively safe during pregnancy, whereas methotrexate, cyclophosphamide, mycophenolate mofetil and leflunomide are contraindicated. Data about the safety of biological agents are scant, but a growing number of publications suggest that at least TNF inhibitors could be prescribed when benefits outweigh the potential risks. Nevertheless, we cannot draw definite conclusions, as this information has not been confirmed in controlled trials. Prospective registries, some of which are already in place, are invaluable resources to answer many questions, especially on the incidence of fetal malformations. Finally, outcome studies on the offspring especially in regard to immune system and psychomotor development will shed light on long-term safety. Keywords: azathioprine, biological agents, cyclosporine, immunosuppressive drugs, leflunomide, methotrexate, mycophenolate mofetil, pregnancy, steroids, TNF inhibitors Expert Opin. Drug Saf. [Early Online]
1.
Introduction
In the past two decades, the number of women suffering from autoimmune and/or inflammatory diseases experiencing one or more pregnancies has significantly increased in parallel with the enormous advances in the diagnosis and management of these disorders and the better knowledge of their pathogenesis. Women affected by rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SSc), Sj€ogren’s syndrome or other systemic inflammatory conditions usually need chronic treatment with immunomodulant or immunosuppressive agents, and the safety of such drugs during pregnancy represents a major concern for both the clinicians and the patients. Information regarding the safety of immunosuppressive drugs during pregnancy is scant, as therapeutic trials exclude pregnant women. The few data available are derived from case reports or case series. In addition to teratogenicity, an important issue that should be taken into consideration for the assessment of safety of this class of drugs concerns potential effects on the development of the immune system of the fetus. Moreover, the need to stop a 10.1517/14740338.2014.951326 © 2014 Informa UK, Ltd. ISSN 1474-0338, e-ISSN 1744-764X All rights reserved: reproduction in whole or in part not permitted
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M. Gerosa et al.
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The proportion of women suffering from autoimmune and/or inflammatory diseases who experience one or more pregnancies has significantly increased in the past two decades. A tight control of autoimmune/inflammatory diseases such as rheumatoid arthritis, systemic lupus erythematosus or inflammatory bowel diseases is important to improve pregnancy outcome in these patients. At present, methotrexate, cyclophosphamide, mycophenolate mofetil and leflunomide are absolutely contraindicated during pregnancy. Azathioprine, cyclosporine, hydroxychloroquine and steroids can be prescribed during pregnancy, if the benefits from treatment outweigh the potential risks. Further data are needed to assess the real safety of biological agents, but maybe TNF inhibitors could be allowed in selected patients with a very severe flare of disease, during the first and second trimester.
This box summarizes key points contained in the article.
potentially harmful treatment at the beginning of pregnancy has to be weighed against the risk of relapse of disease associated with discontinuation. In fact, disease activity at conception and during gestation can strongly affect pregnancy outcome. In SLE patients, the risk of fetal loss in women with active lupus nephritis has been reported to range from 8 to 36%, and active renal involvement or other forms of increased lupus activity in the first and second trimester have been associated with a higher incidence of preterm birth, intrauterine growth restriction (IUGR) and preeclampsia [1]. Relapses of RA or SSc are associated with a lesser risk of adverse pregnancy outcome in comparison to SLE; nevertheless, an active disease has been associated with higher incidence of prematurity and IUGR in these disorders as well [2,3]. Thus, treatment decision-making in women with systemic autoimmune or inflammatory diseases willing to have a baby or who become inadvertently pregnant should evaluate all these aspects. In fact, a very large number of publications suggest that some immunosuppressive drugs, for example, thiopurines or cyclosporine, are relatively safe during pregnancy. On the other hand, several authors report that an active disease during pregnancy may represent a risk factor for congenital abnormalities by itself. Pregnancy in rheumatic patients should be carefully planned and treatment should be chosen in order to achieve the better disease control, together with the lowest risks for the fetus. These patients should be recommended to conceive during a period of longstanding remission, in order to minimize the risks of flare and subsequent adverse pregnancy outcome. Women with autoimmune or inflammatory diseases of childbearing age should undergo multidisciplinary preconceptional counseling for the evaluation of all these aspects. 2
The FDA has created a classification system to define the risk of drug teratogenicity. This classification includes five categories (A, B, C, D and X), considering both the potential risks of and benefits from the drug, with data largely based on animal studies [4]. 2.
Drugs allowed during pregnancy
Glucocorticoids Glucocorticoids (GCs) are the most widely used medications in rheumatic diseases, alone or in combination with other disease-modifying drugs. Non-fluorinated steroids, such as prednisone and prednisolone, commonly used in managing SLE and RA flares, cross the placenta in very low concentrations, whereas fluorinated steroids (betamethasone and dexamethasone) are able to reach the fetal circulation in higher amounts [5]. Studies on animal models have demonstrated that GCs are teratogens in rodents and the oldest studies of antenatal exposure during the first trimester reported an increased incidence of orofacial cleft in humans [6,7]. Nevertheless, data from the literature are not univocal, as several authors reported a 1.7to 3.4-fold increased risk of developing palatal cleft after in utero GC exposure, whereas other studies did not confirm these findings [8-10]. Recently, a Danish population-based study, including > 50,000 exposed pregnancies, did not identify any significant increased risk of orofacial cleft associated with GC use, irrespective of the type of administration [11]. Even if this study adds further evidence of the safety of these molecules, these data should be carefully evaluated. Data about the timing of the use of steroids during pregnancy and the pregnancy outcomes were in fact inferred based on registry data, without personal verification, possibly overestimating the number of women really taking the medication during the first trimester. Taken together, all literature data suggest that GC use during pregnancy is associated with a mild increase of the possibility of orofacial cleft, with an estimated risk of about 1 in 300 live births. In addition to embryotoxicity, several other adverse effects have been associated with steroids during pregnancy. Their administration during the third trimester increases the chance of gestational hypertension and diabetes, osteoporosis, IUGR and preterm delivery due to premature membrane rupture [12]. Moreover, based on studies on animal models suggesting a relationship between prenatal exposure to GCs and altered offspring brain development, several authors have attempted to assess a similar effect in humans [13,14]. A recent study on a large, longitudinal cohort of children prospectively followed up until 16 years of age demonstrated that a single prenatal administration of fluorinated GCs was significantly associated with general psychological disturbances and attention deficit in childhood, after adjustment for relevant confounders [15]. However, neurodevelopment is subject to multiple environmental factors and a true causal relationship in this setting is very hard to assess. 2.1
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Safety considerations when prescribing immunosuppression medication to pregnant women
In rheumatic patients, chronic GC use is associated with reduced bone mineral density (BMD), raising the hypothesis that their use during pregnancy could influence the BMD of the offspring. However, a recent study has evaluated the BMD of 108 children of RA patients and found that prednisone use during pregnancy was not associated with low BMD [16]. In a cohort of women with connective tissue diseases, we have obtained similar results (unpublished data). Antimalarials Antimalarials are widely used for the treatment of rheumatic diseases. Although data from animal models and the first experiments on humans suggested a potential eye and ear toxicity, several further case series demonstrated that chloroquine and hydroxychloroquine (HCQ) are safe and should not be discontinued during pregnancy [17]. Actually, HCQ has been demonstrated to have pleiotropic effects in lupus patients that could be especially noteworthy during pregnancy [18]. HCQ reduces lipid levels and the risk of thromboembolic events in SLE and reduces the risk of lupus flares [18]. Clowse et al. report that discontinuation of HCQ prior to conception is associated with an increased risk of SLE flares [17]. Moreover, it has been recently suggested that prenatal exposure to HCQ decreases the risk of congenital heart block in children of anti-SSA/Ro-positive mothers [19].
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2.2
Azathioprine and cyclosporine Azathioprine and cyclosporine represent the two most common therapeutic options for immunosuppression during pregnancy in rheumatic patients [20]. Their safety has been widely confirmed by the experience in solid organ transplanted women. Initially, large transplant registries had shown that the use of azathioprine during pregnancy was not associated with an increased risk of congenital anomalies [21,22]. Reassuring information are also derived from studies in inflammatory bowel diseases (IBDs). A very large recent meta-analysis demonstrated that azathioprine use during pregnancy was not associated with an increased risk of birth defects, even if there was slightly increased risk of preterm delivery (odds ratio [OR] = 1.67; 95% CI: 1.26, 2.20) in the treated group [23]. More recently, a study on a large population of IBD patients showed a very low rate of major congenital anomalies in children of patients treated with azathioprine, which accounted for an adjusted OR of a major congenital anomaly associated with drug use of 1.27 [24]. Immunosuppression of cyclosporine is mediated by inhibition of lymphocyte proliferation and downregulation of T-helper cell function that leads to decreased secretion of proinflammatory cytokines. As its first indication was prevention of transplant rejection, most of literature data address its safety during pregnancy in women who underwent organ transplantation. Cyclosporine is highly lipophilic and crosses the placenta in great amounts. Nevertheless, a large number of publications including > 5000 pregnancies in transplanted 2.3
women treated with cyclosporine did not show a substantial teratogenic effect. However, a high rate of preeclampsia, preterm delivery and low birth weight in infants has been described. These pregnancy complications were more frequent in kidney- and heart-transplanted women, in comparison to liver and lung transplantations, suggesting a significant effect of the underlying disease and/or preexisting maternal comorbidities [25]. The literature considering cyclosporine safety during pregnancy in autoimmune patients is limited to case reports or case series accounting for about 50 pregnancies. No increased risk of fetal anomalies have been described in these populations, even if again there was a higher incidence of low birth weight and prematurity in comparison to what is expected in the general population (although lower than what is observed in transplanted patients) [20,25]. Studies addressing the potential influence of cyclosporine on the fetal immune system did not show a significant immunosuppressive effect of the drug [26,27]. Cyclosporine is classified in the pregnancy risk category C by the FDA. 3.
Drugs contraindicated during pregnancy
Methotrexate Methotrexate has antiproliferative activity and inhibits DNA synthesis through the inhibition of dihydrofolate reductase [28]. In studies on animal models, the administration of methotrexate during pregnancy was associated with embryolethality in rats and monkeys, whereas an embryotoxic effect was more common in mice and rabbits [28]. In humans, a typical embryopathy, mainly characterized by pulmonary atresia, craniosynostosis and limb deficiencies, had been initially hypothesized with methotrexate exposure [29], and recently confirmed in an exhaustive teratogen update [28]. The sensitive period for the induction of these embryo abnormalities has been recognized between the 6th and the 8th weeks after conception, and the critical levels of maternal drug was suggested to be ‡ 10 mg/week [28]. However, a case of typical methotrexate embryopathy has been very recently described in one of eight pregnancies exposed to a lower dose (7.5 mg weekly) [29]. More recently, a distinct syndrome, including tetralogy of Fallot and possibly neural crest anomalies, has been described for very early (4th week of gestation) high-dose methotrexate treatment for ectopic pregnancy misdiagnosis [30-32]. In 2014, two different studies reporting conflicting results have been published regarding the outcome of methotrexateexposed pregnancies in rheumatic diseases. Cooper et al. [33], in an observational study using claims data from three US health plans, have identified a total of 608 pregnancies in immune-mediated diseases, including 23 patients taking methotrexate during the first trimester of pregnancy. In the methotrexate group, there were no statistical differences regarding the rate of congenital malformations in comparison to pregnancies taking other immunosuppressive medications (TNF inhibitors [TNFi], HCQ, azathioprine, gold, 3.1
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M. Gerosa et al.
sulfasalazine and leflunomide) or patients not exposed to immunosuppression (4.3 vs 2.3% in non-treated women), with a propensity score-adjusted risk ratio (RR) of 1.42. However, fetal deaths occurred most frequently among patients treated with methotrexate (8.7 vs 2.3% in nontreated women), with a RR of 3.18 [33]. Discordant results have been reported by Weber-Schoendorfer et al. [34] in a prospective multicenter cohort study, including 188 pregnancies exposed to methotrexate (median weekly dosage of 10 mg/week, higher weekly dosage of 30 mg/week) after conception and 136 patients who had stopped the drug within 12 weeks before conception. The cumulative incidence of spontaneous abortion in the post-conception exposed cohort was significantly higher than that observed in those who stopped the drug before conception and also in 459 disease-matched non-exposed patients and 1107 non-autoimmune women (42.5 vs 14,4%, 22.5 and 17.3%, respectively). Moreover, there was a significant increase in the rate of birth defects (6.6%) in the methotrexate postconception group in comparison to the non-autoimmune disease cohort (2.9%), whereas the rate of birth defects in the pre-conception treated group and the disease-matched group was lower (3.5 and 3.6%) but not significantly different [34]. In conclusion, even if some recent studies report a lower rate of congenital abnormalities in infants born to mothers exposed to low-dose methotrexate during pregnancy, the drug has to be still considered embryotoxic and should be discontinued at least 12 weeks before conception, as the whole data available in the literature do not suggest that possible benefit outweigh the potential risks (category X of the FDA) [35]. Leflunomide When leflunomide was approved for the treatment of RA, there were major concerns regarding its embryotoxic potential, as it was demonstrated to be highly teratogenic in rats, rabbits and mice [36]. Consequently, it was included in the FDA category X and absolutely contraindicated during pregnancy. Moreover, due to its very long half-life, patients who were planning a pregnancy were advised to discontinue the drug at least 2 years before, and a washout procedure with cholestyramine for 12 days was recommended in case of unintended pregnancy. Given these strong warnings to prevent unintended exposure, data regarding the effect of leflunomide in humans are poor. The first report described the occurrence of severe prematurity, cerebral palsy and unilateral blindness in an infant exposed to leflunomide in utero. However, subsequent studies reported no malformations in 14 exposed pregnancy. Recently, the Organization of Teratology Information Specialists collaborative research group published two prospective, controlled cohort studies comparing the incidence of fetal anomalies in exposed and non-exposed pregnancies in RA patients. Although the authors concluded that leflunomide 3.2
4
exposure did not increase the risk of adverse pregnancy outcome in RA patients after adjustment for confounders, the two studies showed that the rate of major malformations in patients who received at least one dose of leflunomide after conception was 6.9%, which is higher than what was observed in healthy pregnancies [37,38]. Moreover, most of these patients received one or more cholestyramine washout procedures, potentially reducing the risk of its transplacental passage [20,37]. In conclusion, even if this recent data suggest that leflunomide could not be a potent teratogen, the literature is still controversial and washout procedures before conception or in case of unintended pregnancy are recommended [20]. Cyclophosphamide Cyclophosphamide is an alkylating cytotoxic agent that is used for the treatment of hematological malignancies and a variety of solid tumors, but it is also extensively used in the management of severe lupus flares, vasculitis and other connective tissue diseases. It is able to induce ovarian failure depending on the age of the patients and the cumulative dose [39]. Moreover, it has been widely demonstrated to be embryotoxic and teratogen both in animals and humans. There are some case reports of the use of this drug during the second and third trimester without development of malformations, whereas the embryo exposure during the first weeks of gestation has been associated with a high rate of congenital abnormalities that has been included in a characteristic embryopathy by some authors [12,20]. 3.3
Mycophenolate mofetil Mycophenolate mofetil (MMF) is an inhibitor of inosine monophosphate dehydrogenase that exerts its antimetabolite effects via the inhibition of purine synthesis [40]. The drug has been originally approved for the prevention of transplant rejection, but more recently, due to its potent effects on Tand B-lymphocyte proliferation, it has been successfully used in the treatment of autoimmune diseases [40]. MMF has been initially classified as pregnancy category C by the FDA, but several reports of embryo toxicity have led to the reclassification of the drug in category D [41]. Unintended exposure to MMF during pregnancy has been associated with a significant increased risk of miscarriages and also of fetal anomalies [42-45]. Specifically, a typical pattern of abnormalities, including craniofacial malformations, abnormality of distal limbs and heart and esophagus or renal defects, have led to the definition of a characteristic mycophenolate embryopathy [43,44]. In a very recent prospective study evaluating pregnancy outcome in a cohort of liver and cardiothoracic transplant recipients, MMF was significantly associated (OR = 5.3) with poor fetal outcome [45]. In September 2012, the FDA approved a risk evaluation and mitigation strategy (REMS) system to evaluate if the benefits of MMF outweigh the risks [41]. REMS is a process with the aim to mitigate the risk related to a specific drug. The primary objective of REMS is to assess and manage recognized or potential 3.4
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Safety considerations when prescribing immunosuppression medication to pregnant women
significant medication-related risks and to ensure continual pharmacovigilance [46]. Biological agents Biologics are the most recent drugs that have been brought onto the market for the treatment of rheumatic diseases. Due to their relatively recent availability, data regarding their safety during pregnancy are generally poor except for TNFi. The majority of biological agents contain the fragment crystallizable region (Fc) of IgG that is supposed to mediate the active transport of these drugs through the placenta in the fetal circulation, starting from the second trimester [47]. In this regard, Mahadevan et al. have recently demonstrated that levels of infliximab and adalimumab in the blood of neonates that were antenatally exposed to these drugs were comparable or higher than maternal levels at term [47]. In the same study, concentrations of certolizumab pegol, a TNFi that does not contain the Fc fragment, were not detectable in the infant circulation [47]. First data regarding the safety of TNFi were not reassuring, as one study reported a high incidence of congenital abnormalities of the vertebral anomalies, anal atresia, cardiac defects, tracheoesophageal fistula and/or esophageal atresia, renal and radial anomalies and limb (VACTERL) defects spectrum in infants accidentally exposed antenatally to infliximab and etanercept [47]. However, this report should be carefully evaluated because only 1 of the 41 reported abnormalities was consistent with the definition of VACTERL [48]. Accordingly, subsequent data did not confirm these findings, and no further report of VACTERL association abnormalities have been described in TNFi-exposed infants up to now. On the contrary, there is a growing body of evidence that TNFi use during pregnancy is not associated with adverse pregnancy outcomes or congenital malformations [49,50]. A recent systematic review of the literature on 58 publications, including > 1500 pregnancies in IBD patients, has shown that the rate of adverse pregnancy outcome and malformation in treated women is not significantly higher than what is expected in the general population [4]. However, the use of these drugs during the third trimester could interfere with the physiological development of the immune system of the fetus, increasing the risk of neonatal infections [51]. The experiments with the other available biological agents are very limited, mostly related to reports on rituximab use both in lymphoproliferative and in rheumatic diseases. Chakravarty et al. [52] reviewed a total of 153 published cases with a known outcome, reporting 22% of miscarriages, 24% of preterm deliveries and 2.2% of congenital malformations. This review raised a major concern about the effect of antiCD20 therapy on the neonatal immune system, as 4 babies developed severe infections soon after birth and 11 others displayed hematological abnormalities [52]. Since 2011, three additional case reports of women receiving rituximab at the beginning or just before pregnancy have been published [53,54]: two healthy babies and one mildly small for gestational age were the results of these deliveries.
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3.5
Published reports of unintended in utero exposure to abatacept included 10 pregnancies occurring during the open-label phase of a trial on RA and multiple sclerosis [51]. Four ended in spontaneous abortions, three ended in elective terminations and no data are available for the other three. Another report described the successful pregnancy of a woman affected by RA [53]. Current available data on the safety of tocilizumab during pregnancy are scant and have been published so far only in abstract form. Rubbert-Roth et al. reported on 32 pregnancies in RA patients receiving tocilizumab. Thirteen of these patients choose an elective termination and seven experienced a spontaneous abortion. Of the 11 babies, 10 were born at term without pregnancy complications, 1 died of acute respiratory distress syndrome, 3 days after an emergency delivery for obstetrical complications [55]. Belimumab received regulatory approval for the treatment of SLE only in 2011; therefore, very few information is available about its use during pregnancy. GlaxoSmithKline has reported that 83 pregnancies have occurred during placebo-controlled Phase II and Phase III studies. Of these, 27.7% had spontaneous abortions and 24% had an elective termination. Three congenital anomalies occurred in this population (3.6%), but one was associated with a chromosomal translocation that was also found in the mother, and thus was considered to be unrelated to belimumab [18]. The manufacturer has created an online pregnancy registry for the evaluation of pregnancy and infant outcomes in women with SLE exposed to commercially supplied belimumab during pregnancy or in the preceding 4 months. The registry reports that up to now six out of seven pregnancies that occurred during belimumab therapy ended with the birth of healthy babies, even if half of them were preterm. In addition, one of the preterm infants displayed an Ebstein’s anomaly of the cardiac tricuspid valve, a mild congenital heart defect [56]. 4.
Conclusion
With improvements in clinical care, more data on safety of immunosuppressive and antirheumatic treatments during pregnancies have accumulated (Table 1). Several of these drugs, once considered contraindicated during pregnancy, have now been shown to be relatively safe. However, many questions, especially those related to the long-term outcomes in the offspring, are still unanswered. In regard to the new (biologic) drugs, the use of TNFi seems to be relatively safe, even if their use has to be carefully balanced against potential known and yet unknown risks. Considering other biotherapies, they have generally not been used long enough to precisely assess their safety during pregnancy, since the numbers are still small. Different registries are in place in order to evaluate potential side effects (e.g., teratogenicity) and the rarity of these situations make these tools fundamental in order to have reliable answers on frequencies and relative risks of complications.
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5
6
No increase in malformations [17] No increase in malformations [21-24] No increase in malformations [20,25] Typical embryopathyz [28,29] Tetralogy of Fallot and possibly neural crest anomalies [30-32] Inconstant report of increased rate of congenital malformations [36-38] Increased rate of congenital malformations [12,39]
Antimalarials
Expert Opin. Drug Saf. (2014) 13(11)
C X
Low birth weight [25] Cytopenia [28]
Preeclampsia, preterm delivery [25] Abortion, fetal death [33,34]
Miscarriage and prematurity uncertain [52] Miscarriage [51] Miscarriage Spontaneous abortion [18,56]
Not reported
Possible effects on immune system, development of mild increased risk of neonatal infections, no vaccinations during the first 6 months of life [49,51] B-cell depletion, with risk of infections [52] Insufficient available data Insufficient available data Insufficient available data
IUGR, cytopenia, impaired neurological development [12,39] Not reported
Not reported
Not reported
Not reported
Not reported
C C C
C
B
D
D
X
D
C
None
None Preterm delivery [23]
Prednisone B others C
FDA category
IUGR [12], psychological disturbances* [13-15] None
Effects on fetus/infant
Hypertension, diabetes, osteoporosis, PPROM [12]
Pregnancy outcome
*With fluorinated glucocorticoids. z Pulmonary atresia, craniosynostosis and limb abnormalities. § Very few information available about use during pregnancy. IUGR: Intrauterine growth restriction; PPROM: Preterm premature rupture of membrane.
Abatacept§ Tocilizumab§ Belimumab§
Insufficient available data Insufficient available data [55] Increased risk of malformation [18,56]
Insufficient available data
Rituximab
TNF inhibitors
Craniofacial malformations, abnormality of distal limbs and heart and esophagus or renal defects [41-45] No increase in malformations [4,47,49,50]
Mycophenolate mofetil
Cyclophosphamide
Leflunomide
Methotrexate
Cyclosporine
Azathioprine
Mild risk (1/300) of orofacial cleft [8-11]
Teratogenicity
Glucocorticoids
Drug
12 weeks before conception 12 weeks before conception 12 weeks before conception
6 months before
At conception
12 weeks before conception
2 years before conception, washout procedure with cholestyramine recommended 6 months before conception
12 weeks before conception
No
No
No
No
Discontinuation
Table 1. Embryotoxicity and effects on pregnancy outcome and fetus/infant development of glucocorticoids, immunomodulant and immunosuppressive drugs.
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M. Gerosa et al.
Safety considerations when prescribing immunosuppression medication to pregnant women
Expert Opin. Drug Saf. Downloaded from informahealthcare.com by Mcgill University on 10/02/14 For personal use only.
5.
Expert opinion
Information regarding the effects of immunosuppressive drugs on the process of embryogenesis and fetal development are lacking, as therapeutic trials usually exclude pregnant women. The few data available usually derive from case reports of inadvertent drug exposure during unplanned pregnancies. Nevertheless, with time it has been possible to collect more safety data, and several of these drugs such as HCQ, cyclosporine, azathioprine and corticosteroids have been demonstrated not to have relevant effects on embryogenesis and are now allowed during pregnancy. On the contrary, contrasting data are available in the literature regarding other immunosuppressants such as methotrexate, leflunomide and TNFi, as some authors have reported a teratogenic effect of these drugs, whereas other studies do not confirm these findings. The weaknesses of the research mainly depend on the type of studies, since we cannot draw firm conclusion from case reports and case series only. As randomized controlled trials are not feasible due to ethical issues, the collection of data from large-scale, population-based cohorts of women with systemic inflammatory diseases could be a valid alternative for safety assessment. Moreover, we think that prospective registries, some of which are already in place in different parts of the world, are Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.
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Affiliation
Maria Gerosa†1 MD, Pier Luigi Meroni1 & Rolando Cimaz2 † Author for correspondence 1 University of Milan, Ospedale Gaetano Pini, Division of Rheumatology, Department of Clinical Sciences and Community Health, via Pini 9, 20122 Milan, Italy Tel: +390258296719; Fax: +390258296315; E-mail: [email protected] 2 Anna Meyer Children’s Hospital and University of Florence, via Pieraccini 24, 50141, Florence, Italy
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