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treatment during this time. Exogenous corticosteroid use during the first trimester may increase the risk of cleft lip/palate threefold, to an estimated 3/1000 babies (66). When treating the mother with a corticosteroid, prednisone and prednisolone should be used because less than 10% of the dose of these drugs crosses the placenta. Fluorinated steroids, including dexamethasone and betamethasone, easily cross the placenta and should be reserved for treating the foetus (i.e. congenital heart block or to hasten lung maturity prior to a preterm birth). Babies exposed to ongoing dexamethasone or high-dose prednisone treatment in utero may have adrenal insufficiency at birth (67). Although it is optimal to keep daily prednisone to less than 20 mg/day, higher doses are acceptable if they are required to treat aggressive disease. In most situations, the inflammation caused by excessive autoimmune activity is more harmful to the pregnancy than high-dose steroids. Disease-modifying medications Hydroxychloroquine (HCQ; Category C). HCQ can, and should, be continued throughout pregnancy. In more than 300 offspring with in utero HCQ exposure, there has been neither a specific pattern of anomalies nor an increase in congenital anomalies (30, 68). Infants exposed to HCQ in utero have normal electrocardiography (ECG) at birth and normal ophthalmic and auditory examinations after birth (68–70). In addition, HCQ has been shown to decrease the risk for SLE flares and the need for higher doses of corticosteroids (30). Methotrexate (MTX; Category X). MTX, a dihydrofolate reductase inhibitor, is contraindicated during pregnancy and must be stopped 3 months prior to conception because of the risk of pregnancy loss and congenital abnormalities. A specific pattern of central nervous system, craniofacial, and skeletal defects can occur in a foetus exposed to chemotherapy doses of MTX (71). The risk of developing foetal abnormalities at rheumatological doses of MTX (5–25 mg weekly) is less clear. There have been several reports of increased rates of spontaneous abortion and major foetal anomalies, as well as successful pregnancies that result in a healthy infant (72–75). Folic acid should be continued throughout pregnancy for women who have taken MTX prior to pregnancy. MTX is excreted into breast milk and is therefore contraindicated in lactating women (76). Leflunomide (LEF; Category X). LEF, a dihydro-orotate dehydrogenase inhibitor that impairs pyrimidine synthesis, is also contraindicated in pregnancy (77). Animal studies show foetal anomalies at low doses (78). However, the Organization of Teratology Information Specialists (OTIS) followed 63 pregnancies in women with RA exposed to LEF and did not find an increase in miscarriage or foetal malformation compared to 108 pregnancies in woman with RA not exposed to LEF (12). The active metabolite of leflunomide can stay in the body for up to 2 years (79). It is therefore recommended that cholestyramine 8 g three times/day for 11 days be given to women who took LEF prior to conception. Plasma levels less than 0.02 mg/L should be verified by two separate tests performed at least 14 days apart (product information, Arava® oral tablets, 2007). It is not known whether LEF is excreted into breast milk. For this reason it is contraindicated during lactation.Sulfasalazine (SSZ; Category B, D at term).SSZ, a folic acid antagonist, and its metabolite sulfapyridine cross the placenta (80). Animal studies in rats and rabbits have not shown foetal harm at doses six times the human dose (67). Much of the information on SSZ and pregnancy comes from the literature on inflammatory bowel disease (IBD). Observational studies of pregnant women with IBD
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