Rheumatology, Leicester Royal Infirmary, Leicester and 1 Schering Plough, UK
Correspondence to: A. J. Kinder. E-mail: alisonkinder{at}dsl.pipex.com
SIR, A lady was diagnosed with rheumatoid arthritis at the age of 29. She was initially treated with sulphasalazine (3 g/day) and then azathioprine (eventually 250 mg/day) was added. This failed to control her disease, so hydroxychloroquine (400 mg/day) was added. On this combination of drugs (with 5 mg prednisolone and diclofenac 150 mg/day) her disease appeared to be coming under control.
At this point the patient decided she would like to try for a baby. The hydroxychloroquine and sulphasalazine were stopped and the prednisolone was increased to 7.5 mg/day, and she continued on the azathioprine 250 mg/day (with diclofenac 150 mg/day). She tried to conceive for 9 months but was unsuccessful. The infertility clinic found she was not ovulating. Her antiphospholipid antibodies were negative. Her diclofenac (150 mg/day) was stopped and she was commenced on clomifene for infertility. After 2 months of treatment she became pregnant. The baby was stillborn at 36 weeks due to an acute hypoxic event. After several months she again became pregnant on clomifene but miscarried at 15 weeks. She very quickly became pregnant again on clomifene and this time her azathioprine was eventually stopped and her prednisolone was reduced during pregnancy. She gave birth to a healthy boy at 34 weeks. Six months later she became pregnant again on clomifene and gave birth to a girl at 35 weeks. She was restarted on the azathioprine (with prednisolone 7.5 mg/day and diclofenac 150 mg/day) after each pregnancy. The azathioprine (250 mg/day) failed to control the arthritis after her second pregnancy, so it was stopped and she was commenced on methotrexate (eventually at 20 mg/week with folic acid 5 mg/week) in addition to prednisolone 7.5 mg/day and diclofenac 150 mg/day for 12 months. This was ineffective, so infliximab (3 mg/kg) every 8 weeks (after the loading doses) was added to this regime.
Prior to commencing infliximab she was counselled again about avoiding pregnancy and using adequate contraception. Once on infliximab, her disease activity score improved from 6.43 initially to 4.24 at 6 months and her prednisolone was reduced to 5 mg/day. After 9 months on infliximab she became pregnant, which was unplanned. They had been using only condoms for contraception. She discovered she was pregnant at approximately 5 weeks of gestation. She attended the obstetrician, who felt there was high chance of fetal malformation. The patient stopped all medication apart from steroids. As the lady tried to decide whether to proceed with the pregnancy, she suffered a miscarriage at 6 weeks. The miscarriage may have been caused by the methotrexate.
Methotrexate is known to be teratogenic in humans, with the critical period for teratogenicity suspected to be between 6 and 8 weeks after conception [1]. Toxicity to embryonic or trophoblastic tissues is clearly demonstrated by the use of methotrexate to terminate ectopic pregnancies and produce abortions [2]. Methotrexate in high doses (1 mg/kg) in early pregnancy is nearly 88% embryolethal [3], hence its use as a potent abortifacient. The most characteristic malformations induced by methotrexate include craniofacial and limb defects and central nervous system abnormalities, including anencephaly, hydrocephaly and meningomyelocele [4]. It is suggested that the threshold dose of methotrexate required to produce defects is 10 mg weekly [5].
Methotrexate should be discontinued in both males and females at least 3 months before conception because of its prolonged retention in the tissues after discontinuation [6]. The national teratology service and the majority of companies manufacturing methotrexate recommend that methotrexate should be stopped 6 months before conception [5].
Animal studies using infliximab have not revealed fetotoxicity or teratogenicity [7].
Forty-two patients have been treated with infliximab during pregnancy for Crohn's disease and the outcome of the pregnancy is known in 35 women. Of these pregnancies, 26 resulted in live births, and no unexpected teratogenicity has been reported [8]. However, this does not indicate that infliximab is safe during pregnancy and there are insufficient data to advise continuation of infliximab if a patient becomes pregnant [9].
Whether infliximab has any effect on male spermatogenesis is completely unknown.
On commencing infliximab treatment, this lady was rarely having sexual intercourse due to the severity of her rheumatoid arthritis. She consented to using adequate contraception. Since being on infliximab her health status has improved significantly and she has become much more sexually active.
Our main message is that, as young women with severe rheumatoid arthritis receive biological therapy, their overall health status improves significantly and their sex life increases. In addition, in women whose periods have stopped due to chronic disease, once their rheumatoid arthritis is controlled with biological therapy their periods will return. Hence, patients are more likely to become pregnant if not using adequate contraception.
This case highlights the importance of reviewing the continued use of adequate contraception during biological therapy in women of childbearing age, as well as counselling prior to treatment. We know that the combination of infliximab with methotrexate is teratogenic. Newer biological therapies are emerging whose side-effect profile is increasing, but there is certainly no evidence that these are safe in pregnancy.
JE is a Remicare liaison nurse for Ashfield Health Care. She is seconded to Schering-Plough in a non-promotional role. The other authors have declared no conflicts of interest.
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