Ann. N.Y. Acad. Sci. ISSN 0077-8923
A N N A L S O F T H E N E W Y O R K A C A D E M Y O F SC I E N C E S Issue: Steroids in Neuroendocrine Immunology and Therapy of Rheumatic Diseases I
Safety issues of biologics in pregnant patients with rheumatic diseases Monika Østensen National Service for Pregnancy and Rheumatic Diseases, Department of Rheumatology, Trondheim University Hospital, Trondheim, Norway Address for correspondence: Professor Monika Østensen, National Service for Pregnancy and Rheumatic Diseases, Department of Rheumatology, St. Olav’s Hospital, Trondheim University Hospital, Olav Kyrresgt 13, N-7006 Trondheim, Norway. [email protected]
The safety of biologic agents during pregnancy is still being investigated. Tumor necrosis factor ␣ (TNF-␣) inhibitors are the only well-studied biological drugs in pregnancy; they do not appear to be teratogenic but increase the risk of infection after birth when given in late pregnancy. The long-term effects in exposed children are, at present, unknown. An increased risk of infection is a concern for all biologics and the risk increases further should combination with glucocorticoids be necessary. Experiences with rituximab, abatacept, anakinra, tocilizumab, and belimumab in pregnancy are limited. These drugs should be avoided during pregnancy or used only when no other option is available for treatment of serious maternal disease. Keywords: rheumatic disease; pregnancy; biological drugs; glucocorticoids
Introduction With the increasing use of biological drugs in rheumatic and autoimmune diseases, questions about their compatibility with reproduction arise. As a rule, biologic drugs are used in combination with disease-modifying antirheumatic drugs (DMARDs) to increase their efficacy and inhibit the development of neutralizing antibodies.1 Combination therapy may allow for a reduction of required drug doses, thereby decreasing the potential for toxicity. The drug that is most frequently used in combination with biologics is methotrexate (MTX), but leflunomide,2 azathioprine, and cyclosporine3,4 have also been used. Most biologics show better efficacy together with MTX than they do as monotherapy.5 Biologics are complete, or in part, IgG molecules. Fetal exposure to IgG is very low during organogenesis, but placental transfer starts at the beginning of the second trimester and increases until term, when maternal and fetal serum levels are equal or higher in cord serum.6 All biological agents containing the Fc portion of IgG are actively transferred through the placenta by fetal Fc receptors expressed in the trophoblast.7 For biologics that are complete IgG
antibodies, treatment of the mother in the second part of pregnancy can lead to high serum concentrations in cord blood, particularly during exposure near birth. Immunoglobulins have a prolonged halflife in the newborn and disappear from the child´s serum, usually within the first 6 month of life. Tumor necrosis factor ␣ inhibitors Among the tumor necrosis factor (TNF)-␣ inhibitors, infliximab, adalimumab, and golimumab are complete monoclonal antibodies (Table 1). Etanercept is a fusion protein and certolizumab is a pegylated Fab-fragment–binding TNF-␣. All TNF-␣ inhibitors have been classified by the U.S. Food and Drug Administration (FDA) as Category B drugs, meaning that animal reproduction studies have not shown any risk to the fetus, but there are no adequate and well-controlled studies in pregnant women. The published experience with TNF-␣ inhibitors used in humans is presented in Table 1. Most of the exposures have been in the first trimester. In patients planning a pregnancy or in those with active disease that is not responding to a DMARD compatible with pregnancy, TNF-␣ inhibitors should be used with consideration of the differences in doi: 10.1111/nyas.12456
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Table 1. Published experience on human pregnancies exposed to different TNF-␣ inhibitors
TNF-␣ inhibitor type Infliximab: complete IgG1 antibody Etanercept: fusion protein with Fc part Adalimumab: complete IgG1 antibody Golimumab: complete IgG1 antibody Certolizumab: pegylated Fab fragment
Number of human pregnancies exposed
Median percentage of maternal to cord serum level
>1000
160
>500
6
>300
179
Registry data
40
not done
Registry data and case reports
139
3.9
Type of studies Case reports, cohort studies, case-control, registry data Case reports, cohort studies, case-control, registry data Case reports, cohort studies, case-control
placental passage of the anti-TNF-␣ agents. Studies that have compared levels in maternal blood at delivery with cord serum levels show significant differences between mothers and their children for different TNF-␣ inhibitors (Table 1).8 As expected, cord blood levels of complete monoclonal antibodies exceed maternal levels at term, whereas certolizumab, an agent without an Fc region, is barely detectable (Table 1).9 In utero exposure to infliximab after gestational week 30 results in high blood levels in the newborns,8 whereas levels of etanercept are much lower even at treatment throughout pregnancy.10 Cord blood levels of infliximab and adalimumab are lowest when the fetus has been exposed at less than 10 weeks before delivery.11 As the half-life of monoclonal anti-TNF-␣ antibodies is prolonged to several months in newborns, an increased risk of infection in the child exists during late pregnancy exposure, as reported in a 4-month-old child with fatal disseminated bacillus Calmette–Gu´erin (BCG)-itis after BCG vaccination.12 Exposure to TNF-␣ inhibitors has been reported in more than 2000 pregnancies of patients with in-
Effect on pregnancy/child No increase in miscarriage or malformations; no malformation pattern detected No increase in miscarriage or malformations; no malformation pattern detected No increase in miscarriage or malformations; no malformation pattern detected Data not conclusive
No increase in miscarriage or malformations; no malformation pattern detected
flammatory bowel disease (IBD), rheumatic disease, or psoriasis,13,14 and most pregnancy exposures have been in the first trimester. When combining data from case reports, small series, controlled studies, and drug registries on infliximab, etanercept, adalimumab, golimumab, and certolizumab, no significant increased risk of malformations or any consistent pattern of birth defects have been found in exposed versus nonexposed pregnancies.15,16 In a report of pregnancies exposed to TNF-␣ antagonists,17 the high number of congenital anomalies belonging to the VACTERL association could not be confirmed using a populationbased congenital anomaly database or by any casecontrol study.18 Certolizumab (CZP) differs from other antiTNF-␣ monoclonal antibodies in that it has no Fc region and is not actively transported through the placenta.9 A case series of 10 IBD patients who were treated with CZP up to 5 days before delivery showed minimal transplacental transfer.8 On the day of birth, CZP levels in mothers ranged from 1.87 to 59.57 g/mL, whereas those in cord
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blood ranged from below detection level (15 mg/day) use, and even more when the two treatments were combined.56 There are no prospective studies on pregnant patients treated with a combination of biologics and GCs. Furthermore, few biologics have been studied well enough to consider their use in pregnancy. TNF-␣ inhibitors are the only biologic agents with published evidence to support their use during pregnancy, when strictly indicated. Actually, the pregnant women most often treated throughout pregnancy with TNF-␣ inhibitors, and sometimes in combination with GCs, are patients with IBD15 because the underlying disease can be more harmful to pregnancy outcome than the therapy. No excess risks have been reported in women with IBD treated with a combination of TNF-␣ inhibitors and GCs.15 Conclusions The differences in transplacental passage of biological agents relate to their molecular structure. It is most extensive for monoclonal antibodies and less for fusion proteins or drugs that do not contain the Fc part of immunoglobulin. The expert consensus among rheumatologists advocates discontinuing TNF-␣ inhibitors when pregnancy is recognized, except when serious maternal disease demands continuation.41 Published studies of experience with TNF-␣ inhibitors during pregnancy indicate no increase in the malformation rate after first-trimester exposure. However, proof of their long-term safety in the antenatally exposed child is still lacking, which is a reason for caution. From the limited published information, it appears that rituximab is not a strong human teratogen. However, short- or long-term effects of antenatal exposure have not been studied systematically. At this stage, a risk for impaired immune responses or increased susceptibility to infection in exposed children cannot be ruled out.
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The experience with biologics other than TNF-␣ inhibitors during human pregnancy is limited; neither the effects of first-trimester nor late-pregnancy exposure on the child have been sufficiently studied. This is the reason for recommending withdrawal of abatacept, anakinra, TCZ, and belimumab before a planned pregnancy.57 Both biologicals and GCs increase the risk of infection, but no controlled studies on possible adverse effects of this combination in pregnancy have been published. Prolonged use of corticosteroids with doses exceeding 7.5 mg/day can increase side effects in the mother and child. Long-term effects in children have not been studied sufficiently, for either biologics or GCs. When making decisions about therapy in pregnant women, the risk of leaving inflammatory rheumatic disease untreated must be weighed against any maternal or fetal risk associated with the use of medications. Judicious use of biologicals or GCs is indicated when serious maternal disease demands it for the benefit of the mother and fetus. Conflicts of interest The author declares no conflicts of interest. References 1. Jani, M. et al. 2013. The role of DMARDs in reducing the immunogenicity of TNF inhibitors in chronic inflammatory diseases. Rheumatology (Oxford) 53: 213–222. 2. Arida, A. et al. 2011. Anti-TNF agents for Behc¸et’s disease: analysis of published data on 369 patients. Semin. Arthritis Rheum. 41: 61–70. 3. Famenini, S. & J.J. Wu. 2013. Combination therapy with tumor necrosis factor inhibitors in psoriasis treatment. Cutis. 92: 140–147. 4. Murdaca, G., F. Spano` & F. Puppo. 2013. Use of leflunomide plus TNF-␣ inhibitors in rheumatoid arthritis. Expert Opin. Drug Saf. 12: 801–804. 5. Smolen, J.S. et al. 2014. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumaticdrugs: 2013 update. Ann Rheum. Dis. 73: 492–509. 6. Malek, A. et al. 1995. Transport of immunoglobulin G and its subclasses across the in vitro-perfused human placenta. Am. J. Obstet. Gynecol. 173: 760–767. 7. Suzuki, T. et al. 2010. Importance of neonatal FcR in regulating the serum half-life of therapeutic proteins containing the Fc domain of human IgG1: a comparative study of the affinity of monoclonal antibodies and Fc-fusion proteins to human neonatal FcR. J. Immunol. 184: 1968–1976. 8. Mahadevan, U. et al. 2013. Placental transfer of antitumor necrosis factor agents in pregnant patients with inflammatory bowel disease. Clin. Gastroenterol. Hepatol. 11: 286–292.
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9. Nesbitt, T.A. et al. 2007. Effects of structure of conventional anti-TNFs and certolizumabpegol on mode of action in rheumatoid arthritis. Ann. Rheum. Dis. 66(Suppl 2): 296. 10. Murashima, A. et al. 2009. Etanercept during pregnancy and lactation in a patient with rheumatoid arthritis: drug levels in maternal serum, cord blood, breast milk and the infant’s serum. Ann. Rheum. Dis. 68: 1793–1794. 11. Zelinkova, Z. et al. 2013. Effects of discontinuing anti-tumor necrosis factor therapy during pregnancy on the course of inflammatory bowel disease and neonatal exposure. Clin. Gastroenterol. Hepatol. 11: 318–321. 12. Cheent, K. et al. 2010. Case report: fatal case of disseminated BCG infection in an infant born to a mother taking infliximab for Crohn’s disease. J. Crohn. Colitis. 4: 603–605. 13. Berthelot, J.M. et al. 2009. Exposition to anti-TNF drugs during pregnancy: outcome of 15 cases and review of the literature. Joint Bone Spine 76: 28–34. 14. Schnitzler, F. et al. 2011. Outcome of pregnancy in women with inflammatory bowel disease treated with antitumor necrosis factor therapy. Inflamm. Bowel Dis. 17: 1846–1854. 15. Nielsen, O.H., E.V. Jr Loftus & T. Jess. 2013. Safety of TNF-␣inhibitors during IBD pregnancy: a systematic review. BMC Med. 11: 174. 16. Diav-Citrin, O. et al. 2013. Pregnancy outcome following gestational exposure to TNF-alpha-inhibitors: A prospective, comparative, observational study. Reprod. Toxicol. 43C: 78–84. 17. Carter, J.D. et al. 2009. A safety assessment of tumor necrosis factor antagonists during pregnancy: a review of the Food and Drug Administration database. J. Rheumatol. 36: 635– 641. 18. Crijns, H.J. et al. 2011. The distribution of congenital anomalies within the VACTERL association among tumor necrosis factor antagonist-exposed pregnancies is similar to the general population. J. Rheumatol. 38: 1871–1874. 19. Clowse, M. et al. 2012. Outcomes of pregnancy in subjects exposed tocertolizumabpegol. Arthritis Rheum. 64(Suppl 10): S702. 20. Decker, M. et al. 2006. Rituximab plus CHOP for treatment of diffuse large B-cell lymphoma during second trimester of pregnancy. Lancet Oncol. 7: 693–694. 21. Friedrichs, B. et al. 2006. The effects of rituximab treatment during pregnancy on a neonate. Haematologica 91: 1426– 1427. 22. Klink, D.T. et al. 2008. Rituximab administration in third trimester of pregnancy suppress neonatal B-cell development. Clin. Dev. Immunol. 2008: 271363. 23. Gall, B. et al. 2010. Rituximab for management of refractory pregnancy-associated immune thrombocytopenic purpura. J. Obstet. Gynaecol. Can. 32: 1167–1171. 24. Pendergraft, W.F. 3rd. et al. 2013. Fetal outcomes after rituximab exposure in women with autoimmune vasculitis. Ann. Rheum. Dis. 72: 2051–2053. 25. Sangle, S.R. et al. 2013. B-cell depletion therapy and pregnancy outcome in severe, refractory systemic autoimmune diseases. J. Autoimmun. 43: 55–59. 26. Chakravarty, E.F. et al. 2011. Pregnancy outcomes following maternal exposure to rituximab. Blood 117: 1499–506.
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27. Vaidyanathan, A. et al. 2011. Developmental immunotoxicology assessment of rituximab in cynomolgusmonkeys. Toxicol. Sci. 119: 116–125. 28. Ton, E. et al. 2011. Safety of rituximab therapy during twins’ pregnancy. Rheumatology (Oxford). 50:806–808. 29. Kapetanovic, MC. et al. 2014. Impact of anti-rheumatic treatment on immunogenicity of pandemic H1N1 influenza vaccine in patients with arthritis. Arthritis Res. Ther. 16: R2. 30. Eisenberg, R.A. et al. 2013. Rituximab-treated patients have a poor response to influenza vaccination. J. Clin. Immunol. 33: 388–396. 31. Sagnelli, E. et al. 2012. Rituximab-based treatment, HCV replication, and hepatic flares. Clin. Dev. Immunol. 2012: 945950. 32. Pham, T. et al. 2009. Abatacept therapy and safety management. Joint Bone Spine 76(S1): S3–S55. R 33. Kineret Product Monograph. Regulatory Affairs Canada. August 8, 2008. http://www.kineret-eu.com/en/ pro/faq/arifaq36.jsp. 34. Berger, C.T. et al. 2009. A patient’s wish: anakinra in pregnancy. Ann. Rheum. Dis. 68: 1794–1795. 35. Fischer-Betz, R., C. Specker & M. Schneider. 2011. Successful outcome of two pregnancies in patients with adultonset Still’s disease treated with IL-1 receptor antagonist (anakinra). Clin. Exp. Rheumatol. 29: 1021–1023. 36. Pham, T. et al. 2010. Tocilizumab: therapy and safety management. Joint Bone Spine 77(Suppl 1): S3–100. 37. Rubbert-Roth, A. et al. 2010. First experiences with pregnancies in RA patients receiving Tocilizumab therapy [abstract]. Arthritis Rheum. 62: S161. 38. Ishikawa, H. et al. 2012. Pregnancy in patients with rheumatoid arthritis treated with biological agents: results of the 8year of Japanese TBC registry. Ann. Rheum. Dis. 71(Suppl3): 501. 39. Auyeung-Kim, D.J. et al. 2009. Developmental and peripostnatal study in cynomolgus monkeys with belimumab, a monoclonal antibody directed against B-lymphocyte stimulator. Reprod. Toxicol. 28: 443–455. 40. GlaxoSmithKline. 2013. Use of intravenous (IV) benlysta in pregnant patients with systemic lupus erythematosus (SLE). 41. Østensen, M. & F. F¨orger. 2013. How safe are anti-rheumatic drugs in pregnancy? Curr. Op. Pharm. 13: 470–475. 42. Kaufmann, J. et al. 2013. Monotherapy with tocilizumab or TNF-alpha inhibitors in patients with rheumatoid arthritis: efficacy, treatment satisfaction, and persistence in routine clinical practice. Clin. Rheumatol. 32: 1347–1355. 43. Kajantie, E. et al. 2003. Placental 11 beta-hydroxysteroid dehydrogenase-2 and fetal cortisol/cortisone shuttle in small preterm infants. J. Clin. Endocrinol. Metab. 88: 493–500.
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44. Khan, A.A. et al. 2011. Does in utero exposure to synthetic glucocorticoids influence birtahweight, head circumferenceand birth lenght: a systematic review of current evidence in humans. Pediatr. Perinat. Epidemiol. 25: 20–36. 45. Park-Wyllie, L. et al. 2000. Birth defects after maternal exposure to corticosteroids: prospective cohort study and metaanalysis of epidemiological studies. Teratology 6: 385–392. 46. Bay Bjørn, A.M. et al. 2014. Use of corticosteroids in early pregnancy is not associated with risk of oral clefts and other congenital malformations in offspring. Am. J. Ther. 21: 73– 80. 47. Gur, C. et al. 2004. Pregnancy outcome after first trimester exposure to corticosteroids: a prospective controlled study. Reprod. Toxicol. 18: 93–101. 48. de Man, Y.A. et al. 2009. Association of higher rheumatoid arthritis disease activity during pregnancy with lower birth weight: results of a national prospective study. Arthritis Rheum. 60: 3196–3206. 49. Nugent, J.L. et al. 2013. Chronic glucocorticoid exposure potentiates placental chorionic plate artery constriction: implications for aberrant fetoplacental vascular resistance in fetal growth restriction. Endocrinology 154: 876–887. 50. Kurtoglu, S. et al. 2011. Fetal adrenal suppression due to maternal corticosteroid use. J. Clin. Res. Pediatr. Endocrinol. 3: 160–162. 51. de Steenwinkel, F. et al. 2014. The influence of fetal prednisone exposure on the cortisol levels in the offspring. Clin. Endocrinol. (Oxf) 80: 804–810. 52. Deepak, P. Stobaugh, D.J. & Ehrenpreis, E.D. 2013. Infectious complications of TNF-␣ inhibitor monotherapy versus combination therapy with immunomodulators in inflammatory bowel disease: analysis of the Food and Drug Administration Adverse Event Reporting System. J. Gastrointestin. Liver Dis. 22: 269–276. 53. Thamer, M. et al. 2009. Prednisone, lupus activity, and permanent organ damage. J. Rheumatol. 36: 560–564. 54. Danza, A. & G. Ruiz-Irastorza. 2013. Infection risk in systemic lupus erythematosus patients: susceptibility factors and preventive strategies. Lupus 22: 1286–1294. 55. Migita, K. et al. 2013. Rates of serious intracellular infections in autoimmune disease patients receiving initial glucocorticoid therapy. PLoS One 8: e78699. 56. Strangfeld, A. et al. 2011. Treatment benefit or survival of the fittest: what drives the time-dependent decrease in serious infection rates under TNF inhibition and what does this imply for the individual patient? Ann. Rheum. Dis. 70: 1914– 1920. 57. Hyrich, K.L. & Verstappen, S.M. 2013. Biologic therapies and pregnancy: the story so far. Rheumatology (Oxford) DOI: 10.1093/rheumatology/ket409.
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A N N A L S O F T H E N E W Y O R K A C A D E M Y O F SC I E N C E S Issue: Steroids in Neuroendocrine Immunology and Therapy of Rheumatic Diseases I
Safety issues of biologics in pregnant patients with rheumatic diseases Monika Østensen National Service for Pregnancy and Rheumatic Diseases, Department of Rheumatology, Trondheim University Hospital, Trondheim, Norway Address for correspondence: Professor Monika Østensen, National Service for Pregnancy and Rheumatic Diseases, Department of Rheumatology, St. Olav’s Hospital, Trondheim University Hospital, Olav Kyrresgt 13, N-7006 Trondheim, Norway. [email protected]
The safety of biologic agents during pregnancy is still being investigated. Tumor necrosis factor ␣ (TNF-␣) inhibitors are the only well-studied biological drugs in pregnancy; they do not appear to be teratogenic but increase the risk of infection after birth when given in late pregnancy. The long-term effects in exposed children are, at present, unknown. An increased risk of infection is a concern for all biologics and the risk increases further should combination with glucocorticoids be necessary. Experiences with rituximab, abatacept, anakinra, tocilizumab, and belimumab in pregnancy are limited. These drugs should be avoided during pregnancy or used only when no other option is available for treatment of serious maternal disease. Keywords: rheumatic disease; pregnancy; biological drugs; glucocorticoids
Introduction With the increasing use of biological drugs in rheumatic and autoimmune diseases, questions about their compatibility with reproduction arise. As a rule, biologic drugs are used in combination with disease-modifying antirheumatic drugs (DMARDs) to increase their efficacy and inhibit the development of neutralizing antibodies.1 Combination therapy may allow for a reduction of required drug doses, thereby decreasing the potential for toxicity. The drug that is most frequently used in combination with biologics is methotrexate (MTX), but leflunomide,2 azathioprine, and cyclosporine3,4 have also been used. Most biologics show better efficacy together with MTX than they do as monotherapy.5 Biologics are complete, or in part, IgG molecules. Fetal exposure to IgG is very low during organogenesis, but placental transfer starts at the beginning of the second trimester and increases until term, when maternal and fetal serum levels are equal or higher in cord serum.6 All biological agents containing the Fc portion of IgG are actively transferred through the placenta by fetal Fc receptors expressed in the trophoblast.7 For biologics that are complete IgG
antibodies, treatment of the mother in the second part of pregnancy can lead to high serum concentrations in cord blood, particularly during exposure near birth. Immunoglobulins have a prolonged halflife in the newborn and disappear from the child´s serum, usually within the first 6 month of life. Tumor necrosis factor ␣ inhibitors Among the tumor necrosis factor (TNF)-␣ inhibitors, infliximab, adalimumab, and golimumab are complete monoclonal antibodies (Table 1). Etanercept is a fusion protein and certolizumab is a pegylated Fab-fragment–binding TNF-␣. All TNF-␣ inhibitors have been classified by the U.S. Food and Drug Administration (FDA) as Category B drugs, meaning that animal reproduction studies have not shown any risk to the fetus, but there are no adequate and well-controlled studies in pregnant women. The published experience with TNF-␣ inhibitors used in humans is presented in Table 1. Most of the exposures have been in the first trimester. In patients planning a pregnancy or in those with active disease that is not responding to a DMARD compatible with pregnancy, TNF-␣ inhibitors should be used with consideration of the differences in doi: 10.1111/nyas.12456
32
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Biologics and corticosteroids
Table 1. Published experience on human pregnancies exposed to different TNF-␣ inhibitors
TNF-␣ inhibitor type Infliximab: complete IgG1 antibody Etanercept: fusion protein with Fc part Adalimumab: complete IgG1 antibody Golimumab: complete IgG1 antibody Certolizumab: pegylated Fab fragment
Number of human pregnancies exposed
Median percentage of maternal to cord serum level
>1000
160
>500
6
>300
179
Registry data
40
not done
Registry data and case reports
139
3.9
Type of studies Case reports, cohort studies, case-control, registry data Case reports, cohort studies, case-control, registry data Case reports, cohort studies, case-control
placental passage of the anti-TNF-␣ agents. Studies that have compared levels in maternal blood at delivery with cord serum levels show significant differences between mothers and their children for different TNF-␣ inhibitors (Table 1).8 As expected, cord blood levels of complete monoclonal antibodies exceed maternal levels at term, whereas certolizumab, an agent without an Fc region, is barely detectable (Table 1).9 In utero exposure to infliximab after gestational week 30 results in high blood levels in the newborns,8 whereas levels of etanercept are much lower even at treatment throughout pregnancy.10 Cord blood levels of infliximab and adalimumab are lowest when the fetus has been exposed at less than 10 weeks before delivery.11 As the half-life of monoclonal anti-TNF-␣ antibodies is prolonged to several months in newborns, an increased risk of infection in the child exists during late pregnancy exposure, as reported in a 4-month-old child with fatal disseminated bacillus Calmette–Gu´erin (BCG)-itis after BCG vaccination.12 Exposure to TNF-␣ inhibitors has been reported in more than 2000 pregnancies of patients with in-
Effect on pregnancy/child No increase in miscarriage or malformations; no malformation pattern detected No increase in miscarriage or malformations; no malformation pattern detected No increase in miscarriage or malformations; no malformation pattern detected Data not conclusive
No increase in miscarriage or malformations; no malformation pattern detected
flammatory bowel disease (IBD), rheumatic disease, or psoriasis,13,14 and most pregnancy exposures have been in the first trimester. When combining data from case reports, small series, controlled studies, and drug registries on infliximab, etanercept, adalimumab, golimumab, and certolizumab, no significant increased risk of malformations or any consistent pattern of birth defects have been found in exposed versus nonexposed pregnancies.15,16 In a report of pregnancies exposed to TNF-␣ antagonists,17 the high number of congenital anomalies belonging to the VACTERL association could not be confirmed using a populationbased congenital anomaly database or by any casecontrol study.18 Certolizumab (CZP) differs from other antiTNF-␣ monoclonal antibodies in that it has no Fc region and is not actively transported through the placenta.9 A case series of 10 IBD patients who were treated with CZP up to 5 days before delivery showed minimal transplacental transfer.8 On the day of birth, CZP levels in mothers ranged from 1.87 to 59.57 g/mL, whereas those in cord
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blood ranged from below detection level (15 mg/day) use, and even more when the two treatments were combined.56 There are no prospective studies on pregnant patients treated with a combination of biologics and GCs. Furthermore, few biologics have been studied well enough to consider their use in pregnancy. TNF-␣ inhibitors are the only biologic agents with published evidence to support their use during pregnancy, when strictly indicated. Actually, the pregnant women most often treated throughout pregnancy with TNF-␣ inhibitors, and sometimes in combination with GCs, are patients with IBD15 because the underlying disease can be more harmful to pregnancy outcome than the therapy. No excess risks have been reported in women with IBD treated with a combination of TNF-␣ inhibitors and GCs.15 Conclusions The differences in transplacental passage of biological agents relate to their molecular structure. It is most extensive for monoclonal antibodies and less for fusion proteins or drugs that do not contain the Fc part of immunoglobulin. The expert consensus among rheumatologists advocates discontinuing TNF-␣ inhibitors when pregnancy is recognized, except when serious maternal disease demands continuation.41 Published studies of experience with TNF-␣ inhibitors during pregnancy indicate no increase in the malformation rate after first-trimester exposure. However, proof of their long-term safety in the antenatally exposed child is still lacking, which is a reason for caution. From the limited published information, it appears that rituximab is not a strong human teratogen. However, short- or long-term effects of antenatal exposure have not been studied systematically. At this stage, a risk for impaired immune responses or increased susceptibility to infection in exposed children cannot be ruled out.
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The experience with biologics other than TNF-␣ inhibitors during human pregnancy is limited; neither the effects of first-trimester nor late-pregnancy exposure on the child have been sufficiently studied. This is the reason for recommending withdrawal of abatacept, anakinra, TCZ, and belimumab before a planned pregnancy.57 Both biologicals and GCs increase the risk of infection, but no controlled studies on possible adverse effects of this combination in pregnancy have been published. Prolonged use of corticosteroids with doses exceeding 7.5 mg/day can increase side effects in the mother and child. Long-term effects in children have not been studied sufficiently, for either biologics or GCs. When making decisions about therapy in pregnant women, the risk of leaving inflammatory rheumatic disease untreated must be weighed against any maternal or fetal risk associated with the use of medications. Judicious use of biologicals or GCs is indicated when serious maternal disease demands it for the benefit of the mother and fetus. Conflicts of interest The author declares no conflicts of interest. References 1. Jani, M. et al. 2013. The role of DMARDs in reducing the immunogenicity of TNF inhibitors in chronic inflammatory diseases. Rheumatology (Oxford) 53: 213–222. 2. Arida, A. et al. 2011. Anti-TNF agents for Behc¸et’s disease: analysis of published data on 369 patients. Semin. Arthritis Rheum. 41: 61–70. 3. Famenini, S. & J.J. Wu. 2013. Combination therapy with tumor necrosis factor inhibitors in psoriasis treatment. Cutis. 92: 140–147. 4. Murdaca, G., F. Spano` & F. Puppo. 2013. Use of leflunomide plus TNF-␣ inhibitors in rheumatoid arthritis. Expert Opin. Drug Saf. 12: 801–804. 5. Smolen, J.S. et al. 2014. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumaticdrugs: 2013 update. Ann Rheum. Dis. 73: 492–509. 6. Malek, A. et al. 1995. Transport of immunoglobulin G and its subclasses across the in vitro-perfused human placenta. Am. J. Obstet. Gynecol. 173: 760–767. 7. Suzuki, T. et al. 2010. Importance of neonatal FcR in regulating the serum half-life of therapeutic proteins containing the Fc domain of human IgG1: a comparative study of the affinity of monoclonal antibodies and Fc-fusion proteins to human neonatal FcR. J. Immunol. 184: 1968–1976. 8. Mahadevan, U. et al. 2013. Placental transfer of antitumor necrosis factor agents in pregnant patients with inflammatory bowel disease. Clin. Gastroenterol. Hepatol. 11: 286–292.
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