|Year : 2016 | Volume
| Issue : 6 | Page : 156-162
Nonbiologic disease-modifying antirheumatic drugs in pregnancy
Durga Prasanna Misra, Jignesh Babulal Usdadiya, Vir Singh Negi
Department of Clinical Immunology, JIPMER, Puducherry, India
|Date of Web Publication||22-Nov-2016|
Durga Prasanna Misra
Department of Clinical Immunology, JIPMER, Puducherry - 605 006
Source of Support: None, Conflict of Interest: None
Rheumatic disease often affects young females and males in the reproductive age group. Management of these diseases with immunosuppressive disease-modifying antirheumatic drugs (DMARDs) is fraught with potential risks for the developing fetus as well as adverse pregnancy outcomes. In developing countries like India, most patients are treated with conventional DMARDs. We reviewed recent literature on safety during pregnancy for conventional disease-modifying agents, in view of the recently published landmark guidelines of the British Society for Rheumatology and the European League against Rheumatism. Exposure to leflunomide and cyclophosphamide is contraindicated in mothers during pregnancy and preconception phase, and fathers during conception due to risks for the developing fetus. Maternal exposure to methotrexate (MTX) during pregnancy or preconception confers higher risk of adverse pregnancy and fetal outcomes although paternal exposure may not be harmful. Sulfasalazine is safe during pregnancy; however, paternal exposure may reduce fertility, but this is reversible with cessation of the drug. Hydroxychloroquine, azathioprine, cyclosporine, and tacrolimus are compatible with maternal and paternal exposures without evidence for increased risk to the developing fetus. Insufficient data exist regarding safety profile of tofacitinib and apremilast during pregnancy. Rheumatologists should be cautious while starting these drugs in women and men of reproductive age group, and counsel patients accordingly to minimize the risk of adverse fetomaternal outcomes.
Keywords: Cyclophosphamide, leflunomide, methotrexate, mycophenolate mofetil, non-biologic DMARDs, pregnancy
|How to cite this article:|
Misra DP, Usdadiya JB, Negi VS. Nonbiologic disease-modifying antirheumatic drugs in pregnancy. Indian J Rheumatol 2016;11, Suppl S2:156-62
| Introduction|| |
Many rheumatic diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) are common in young females in the childbearing age. Management of these diseases in these patients represents a balancing act between the consequences of potential disease-related damage and the risk of infertility or adverse pregnancy outcomes when treated with potent immunosuppressive agents. Young males in the reproductive age group may also be affected with rheumatic diseases such as spondyloarthropathies and require disease-modifying antirheumatic drugs (DMARDs). Effect of these drugs on testicular function may result in impaired fertility, and excretion in the semen may adversely affect the fetus in the event of conception. Most patients in developing countries like India are treated with conventional DMARDs (cDMARDs) since financial considerations preclude the use of biologic DMARDs in a majority of the patients. Because it is difficult to conduct a randomized trial regarding pregnancy outcomes in patients exposed to DMARDs, most of the inferences regarding safety (or the lack thereof) are drawn from animal experiments and analyses of retrospective data (including databases of patients who have received these medications for solid organ transplantation or inflammatory bowel disease). Literature suggests that in spite of awareness of recommendations for DMARD use among rheumatologists and obstetricians,  a significant number of women continue to receive potentially dangerous teratogens during the first trimester of pregnancy (during which organogenesis occurs, and hence the developing fetus is at the greatest risk of congenital malformations) or the 3 months preceding it.  We shall review the literature on the use of cDMARDs, i.e., MTX, sulfasalazine (SSZ), leflunomide, hydroxychloroquine, azathioprine (AZA), mycophenolate, cyclosporine, tacrolimus, cyclophosphamide (CYC), tofacitinib, and apremilast in relation to pregnancy.
| Search Strategy|| |
We searched MEDLINE and Google Scholar databases using the key words "pregnancy" in combination with each of "MTX," "SSZ," "leflunomide," "hydroxychloroquine," "AZA," "mycophenolate," "cyclosporine," "tacrolimus," "CYC," "tofacitinib" and "apremilast," for articles published from 2000 onward. Article titles and abstracts were read before deciding to include the articles in the review. In addition, the recently published landmark guidelines of the British Society for Rheumatology (BSR)  and the European League against Rheumatism  regarding the use of drugs in pregnancy in women with rheumatic diseases were also consulted. We shall present our findings individually for each drug, focusing on those drugs where the literature is controversial or suggests predominantly higher risk of adverse pregnancy outcomes with use of the drug.
| Hydroxychloroquine|| |
Hydroxycholoroquine is a commonly used DMARD in patients with lupus, RA, and dermatomyositis. It is considered to be safe in pregnancy and is also compatible with paternal exposure at the time of conception. ,
| Methotrexate|| |
MTX is commonly used in patients with RA, Sjogren's syndrome (SS), and lupus. MTX is considered a teratogenic drug. Studies in animals have demonstrated an embryotoxic effect and exposures in early pregnancy have been associated with the so-called MTX embryopathy, which includes growth retardation, cranial and skeletal abnormalities as well as neural crest defects including endocardial cushion defects such as tetralogy of Fallot.  It is recommended that it should be withdrawn at least 3 months before conception.  Accidental exposure to MTX in the last 3 months preconception or during the period of pregnancy requires to be treated with daily folic acid (5 mg) during pregnancy.  However, a lot of recent literature suggests that pregnancy outcomes in patients exposed to MTX during this period may not be uniformly bad [Table 1].
|Table 1: Summary of recent studies on maternal and paternal exposure to methotrexate (MTX) and pregnancy outcomes|
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Brouwer et al.  analyzed prospectively collected data from the Netherlands and reported no significant increase in time to attaining pregnancy in women with RA treated previously with MTX. Vinet et al.  reported a lower rate of induced abortions in women receiving MTX compared to those not exposed to MTX in the 16 weeks before abortion (odds ratio: [OR] 0.47, 95% confidence interval [CI]: 0.25-0.89), in their analysis of a Canadian database of 18,654 women with RA. While this might seem reassuring, it must be interpreted in the context of the alternative explanation of potentially increased spontaneous abortions in the subgroup of patients with RA receiving MTX. Weber-Schoendorfer et al.  analyzed a trans-Atlantic database incorporating data on pregnancies for patients with RA exposed to MTX (324, of whom 136 were exposed preconception and 188 were exposed postconception), other autoimmune diseases not exposed to MTX (disease controls, n = 459) and unexposed healthy controls (n = 1107). The preconception cohort did not show a significantly higher incidence of spontaneous abortions or major birth defects to either disease controls or healthy controls. However, the postconception cohort had a higher risk of spontaneous abortions (adjusted heart rate: 2.1, 95% CI: 1.3-3.2 compared to disease controls) as well as major birth defects (OR: 3.1, 95% CI: 1.03-9.5 compared with healthy controls; the adjusted OR for comparison with disease controls was not significant [OR: 1.8, 95% CI: 0.6-5.7]). Cooper et al.  reported the outcomes of 608 pregnancies from a database of patients from California. 402 of these fetuses had exposure to immunosuppressive agents, including MTX, during the first trimester, and 5.2% of them developed major congenital malformations compared to 2.3% of those fetuses (n = 171) who had not been exposed to immunosuppressants during the first trimester of pregnancy. Overall, there were 10 fetal deaths, 113 preterm deliveries, and 485 term deliveries. Exposure to MTX, hydroxychloroquine, tumor necrosis factor inhibitors, or other immunosuppressants (taken together) was not associated with significant relative risk (RR) of adverse fetal outcomes (congenital malformations, fetal death, or neonatal complications resulting from either a term or a per-term delivery). However, caution must be exercised in drawing conclusions about the safety of MTX exposure in pregnancy in view of the small number of patients (n = 23), variable duration of exposure, as well as wide CIs for the RRs described in the study. Viktil et al.  analyzed pregnancy outcomes retrospectively from a Norwegian database of 154,976 pregnancies, of whom 1461 had received DMARDs. Eight women had received MTX (including seven in the preconception period and two in the first trimester), and fifty fathers had been dispensed MTX in the preconception period. Whereas none of the maternal exposures resulted in congenital malformation, two of the children sired by fathers exposed to MTX had orofacial abnormalities. In contrast, Weber-Schoendorfer et al.,  in a retrospective analysis of a German database, found no increase in adverse outcomes (spontaneous abortions, stillbirths, all birth defects, major birth defects, or chromosomal abnormalities) resulting from paternal exposures to MTX in the preconception period (n = 113) compared with 412 pregnancies, in which the partner had not been exposed to MTX. However, paternal exposure to MTX was associated with a higher incidence of preterm deliveries. Similar findings were reported by Wallenius et al.  in their retrospective analysis of a Norwegian database. They found no increase in adverse pregnancy outcomes or fetal malformations in the 110 fathers exposed to DMARDs preconception (including 49 of whom who received MTX) compared to 230 fathers not exposed to MTX. On the basis of available literature, the BSR guidelines cautiously suggested that paternal exposure to MTX may not be associated with adverse fetal outcomes. 
| Sulfasalazine|| |
SSZ is considered to be safe during pregnancy, when taken along with daily folate supplementation of 5 mg daily.  In rats exposed to SSZ, decreased expression of CD59 and decay accelerating factor in the epididymis  and increased oxidative stress in the testes and epididymis  have been found to contribute toward impaired sperm maturation and functional defect in the form of diminished acrosomal reaction. In patients with inflammatory bowel disease, paternal exposure to SSZ has been associated with abnormal sperm morphology and low sperm counts in seminal fluid, associated with reduction in serum testosterone levels and higher levels of luteinizing hormone compared to healthy controls.  Reduced fertility associated with the use of SSZ in men is considered reversible 3 months after stopping therapy. Infertility is not common and it may not be necessary to stop SSZ unless infertility of 12 months duration or more is observed. 
| Leflunomide|| |
Leflunomide is a DMARD commonly used in RA and psoriatic arthritis (PsA). It has been proven to be teratogenic in animal models. Mice exposed to leflunomide during the period of organogenesis have been shown to develop limb abnormalities, cranial and skeletal malformations, and cardiac defects.  Exposure to leflunomide is associated with decreased mitosis of mesenchymal stem cells in the limb bud in these animal models. 
Two reports from the Organization of Teratology Information Specialists (OTIS) research group have further explored the risk of teratogenicity of leflunomide in a prospective cohort of patients from North America. The first study  compared outcomes in 64 women exposed to leflunomide in the first trimester of pregnancy with 108 disease controls (women with RA or juvenile idiopathic arthritis not exposed to leflunomide or any other known teratogenic agent during pregnancy) and 78 healthy controls. More than 95% of the mothers exposed to leflunomide had received cholestyramine washout. Although children born by patients on leflunomide had lower gestational age and lower birth weight and were more likely to be born by cesarean section, there were no significant increases in preterm delivery, low birth weight, nor was there any increase in major or minor congenital malformations. The second study from this group  compared outcomes in 29 mothers exposed to leflunomide before conception and 16 mothers who had received leflunomide during the first trimester of pregnancy. About three-fourth of these women had undergone leflunomide washout after the detection of pregnancy. The women who had received leflunomide during pregnancy had a higher incidence of preterm delivery, and two of them reported major congenital abnormalities (one with aplasia cutis of thighs, the other with multiple skeletal, craniofacial, and cardiac anomalies). A retrospective analysis of a large Norwegian database  analyzed three mothers who had been exposed to leflunomide (one preconception, two during pregnancy) and one father exposed to leflunomide during the time of conception. None of these exposures resulted in congenital malformations. Another analysis from this same database  reported no adverse outcomes in fathers exposed to DMARDs during conception, a minority of whom had received leflunomide. While this may suggest that exposure to leflunomide in the preconception period may be compatible with a normal or near-normal pregnancy and fetal outcome in the majority, it is strongly recommended to stop at least 3 months before trying for a baby in women and to have a cholestyramine washout unless deferring pregnancy for at least 2 years. Accidental exposure during pregnancy should also be washed out with cholestyramine until the plasma levels of leflunomide are undetectable. Such precautions may not be needed in fathers planning a family. 
| Azathioprine|| |
AZA is a DMARD often used in lupus and systemic vasculitis. It is considered safe during pregnancy when used at doses ≤2 mg/kg/day and is not contraindicated in the father at the time of conception.  Saavedra et al.  retrospectively analyzed pregnancy outcomes in 178 females (87 exposed to AZA during pregnancy, 91 not exposed) and found no difference with respect to pregnancy outcomes or congenital anomalies. Recent retrospective analyses of patients with lupus nephritis have confirmed no increase in adverse pregnancy outcomes or disease flares after switching treatment from mycophenolate mofetil (MMF) to AZA before conception. ,
| Mycophenolate Mofetil|| |
MMF is used as an induction agent in lupus and as a maintenance agent in patients with lupus and vasculitis. Animal studies have shown teratogenic effects resulting from intake of MMF during early pregnancy, with hydrocephalus, anophthalmia, cardiac abnormalities, and renal abnormalities being described in these mice. Much of the teratogenic effects of MMF in humans have been reported from solid organ transplant patients. Hoeltzenbein et al.  prospectively analyzed an European database to identify 57 mothers exposed to MMF during pregnancy, with resultant 16 spontaneous abortions, 12 induced abortions, and 29 live childbirths. Six of these 29 neonates had major congenital abnormalities, including external auditory canal atresia, tracheoesophageal atresia, myelomeningocele, hydronephrosis, and cardiac septal defects. Sifontis et al.  analyzed data from the National Transplantation Pregnancy Registry (USA) and reported outcomes in 33 pregnancies exposed to MMF. There were 15 spontaneous abortions (45%); four out of the remaining 18 live births had major congenital malformations, including skeletal abnormalities, microtia, cleft lip, and cleft palate. In view of the significant risk of the adverse fetal outcome in pregnant women exposed to MMF, it is recommended that MMF should be stopped at least 6 weeks before attempting conception and during pregnancy.  Jones et al.  analyzed 205 pregnancies fathered by 152 transplant recipients exposed to mycophenolic acid from the National Transplantation Pregnancy Registry and found no increase in adverse pregnancy outcomes compared to the general population. Hence, the BSR guidelines suggest that exposure to MMF in the father may be compatible with a normal pregnancy. 
| Calcineurin Inhibitors|| |
Cyclosporine and tacrolimus are used as induction and maintenance agents in lupus nephritis. Literature on the use of these drugs during pregnancy has been drawn mostly from experiences in solid organ transplantation,  and they are considered compatible with pregnancy as well as for paternal exposure.  However, the careful monitoring will be required during a pregnancy in a woman taking these drugs. 
| Cyclophosphamide|| |
CYC is used as a first-line agent for the induction of remission in lupus nephritis and primary systemic vasculitis. Exposure to CYC can result in teratogenicity  as well as gonadal failure, which needs to be kept in mind while prescribing in young patients (both females and males). A 3-fold greater risk of gonadal failure has been described in women older than 24 years receiving CYC compared to younger women  although other studies have suggested that the risk is greatest in those aged 30 years or more. However, should patients receiving CYC not experience gonadal failure; they can have successful pregnancies in the future. Croft et al.  reported 13 pregnancies in 11 women who had been treated with CYC (median cumulative dose 6 g) for antineutrophil cytoplasmic antibody vasculitis who had successful pregnancy outcomes. Two of them required the aid of assistive reproduction technologies, whereas the remaining eleven conceived spontaneously. All pregnancies continued till term, and all neonates born were morphologically normal. Alarfaj and Khalil  retrospectively reviewed data on pregnancies in a large cohort of patients with SLE who had received CYC. They reported older age of exposure, higher cumulative dose and duration of CYC, and more number of cycles of CYC as risk factors for amenorrhea. Women who could not conceive after receiving CYC had received a higher cumulative dose (mean 8.3 g vs. 6.7 gram) and were exposed to CYC at an older age (mean 34 years vs. 28 years) compared to those who were able to conceive after therapy with CYC. Logistic regression analysis revealed that the older age of therapy with CYC was a risk factor for inability to conceive after CYC exposure (RR: 1.16, 95% CI: 1.03-1.32). They also compared pregnancy outcomes in patients with lupus who had received CYC compared to those who had not and found that although the frequency of preterm deliveries was higher in patients receiving CYC, they did not differ with respect to the proportions of live births or neonates with intrauterine growth retardation. A recently published analysis of 10,938 cancer survivors  from the USA concluded that cumulative doses of CYC ≥11295 mg/m 2 in females and ≥7412 mg/m 2 in males conferred higher risk of infertility. Hence, it is recommended that CYC should be used during pregnancy only in life-threatening or severe disease and parental exposure should be avoided if possible.  Strategies such as administration of gonadotropin analogs to induce temporary cessation of menstrual cycles during the administration of CYC have reported mixed results.  Somers et al.  studied the development of premature ovarian failure in patients with lupus requiring CYC therapy treated with monthly gonadotrophin analog compared with a control group of lupus patients not receiving this treatment along with CYC. They found that the only one out of the twenty patients receiving gonadotrophin analog developed premature ovarian failure, in comparison to six out of twenty patients in the control group. The alternative method of oocyte storage before CYC therapy presents challenges in patients with lupus, including the risk of lupus flares during ovarian stimulation.  Hence, the use of gonadotropin analogs may be a reasonable alternative approach toward maintaining ovulation in these patients.  Male patients who want to increase chances of fathering a child in the future should consider sperm banking before exposure to CYC. 
| Tofacitinib|| |
Tofacitinib, an oral janus kinase inhibitor, has recently garnered evidence for use in RA and PsA. A recent paper analyzed data regarding maternal and paternal exposures to tofacitinib from the clinical trials database of Pfizer and the OTIS registry.  Forty-six maternal exposures to tofacitinib (13 in combination with MTX) were reported. Six were lost to follow-up, 25 had normal pregnancy outcomes, eight had induced abortions, seven spontaneous abortions, and one child had congenital pulmonary stenosis. Of the 44 fathers exposed to tofacitinib (one in combination with MTX), outcomes were reported in 28 pregnancies (23 normal deliveries with healthy neonates, five spontaneous abortions). It was concluded that insufficient data exist regarding the use of tofacitinib in pregnancy to draw definite conclusions.
| Apremilast|| |
Apremilast is an oral phosphodiesterase 4 inhibitor used in PsA and Behcet's disease and undergoing trials in other inflammatory arthritides.  We could not find data regarding the use of apremilast in pregnant women, and this requires exploration as more information becomes available regarding the use of this drug.
| Conclusion|| |
MTX and leflunomide may be associated with adverse pregnancy outcomes due to maternal exposure. There is less evidence of adverse outcomes with paternal exposure, but these drugs are best avoided before conception in women and men wanting to have children and during pregnancy. Mycophenolate is clearly associated with adverse pregnancy outcomes with maternal but to date not paternal exposures. CYC confers high risk of infertility in both males and females, which is associated with cumulative dose and age at exposure and is associated with teratogenicity during in-utero exposure. SSZ is safe during pregnancy, but is associated with reversible male infertility due to its effects on sperm maturation. Hydroxychloroquine, AZA, cyclosporine and tacrolimus are compatible with pregnancy. Insufficient literature exists regarding use of tofacitinib and apremilast in pregnancy. Clinicians must be cautious while prescribing these drugs to males and females in the reproductive age group to minimize the risk of adverse pregnancy and fetal outcomes.
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Conflicts of interest
There are no conflicts of interest.
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