Methotrexate (MTX) is the first-line disease-modifying antirheumatic drug (DMARD) for RA. MTX inhibits dihydrofolate reductase, thus interfering with folic acid metabolism and purine synthesis. Closure of the neural tube occurs during the fifth week of pregnancy; the embryo is therefore probably most vulnerable to antifolate drugs at this time. Thus, early folic acid supplementation is essential and should be continued during the preconception period, even after methotrexate is stopped, and should be continued throughout pregnancy. High-dose MTX crosses the placenta, is teratogenic, and is classified as a category X drug in pregnancy. Exposure to low doses (20 mg or less weekly, as used in the rheumatology setting) has been associated with a high rate (20 %) of spontaneous abortions [103].

Oral methotrexate has a half-life of 3–10 h, but can persist in the liver for several months after discontinuation. We recommend stopping MTX 3–4 months before conception to allow adequate time for elimination of the drug.

MTX is excreted into breast milk in low concentrations [104]. The significance of this small amount for the nursing child is unknown, but should be avoided due to theoretical risks.

Leflunomide is used to treat patients with moderate to severe RA. It is an inhibitor of dihydroorotate dehydrogenase and pyrimidine synthesis. It was shown to be teratogenic in rats, rabbits, and mice and therefore labeled as a category X drug. Leflunomide has a half-life of 14 days, but its active metabolite undergoes enterohepatic circulation and may persist in the body for up to 2 years. A dosing regimen of cholestyramine has been described to reduce levels rapidly in less than 14 days [105].

The Organization of Teratology Information Specialists (OTIS) published the results of a prospective study of birth outcomes in women exposed before or during pregnancy to leflunomide. Compared with unexposed RA pregnancies, there was neither increase in birth defects nor any recognizable malformation pattern [106]. This result was confirmed in additional 45 pregnancies of patients who were exposed to leflunomide either within 2 years before conception or during the first trimester [107]. These data indicate that leflunomide is not a strong human teratogen. Nevertheless, due to the limited number of exposed pregnancies in these studies, safe and effective contraception is recommended while taking leflunomide, and a cholestyramine washout procedure should be done in the setting of a planned or unintended pregnancy.

No data exist on excretion into breast milk; breastfeeding is therefore not recommended.

Cyclophosphamide (CYC) is an alkylating agent commonly used for the treatment of malignancies, lupus nephritis, and vasculitis. It inhibits cell division and is teratogenic. Exposure to CYC early in pregnancy in several animal species and humans is associated with a severe embryopathy that includes craniosynostosis, facial anomalies, distal limb defects, and developmental delay [108]. Clowse et al. reported unfavorable outcomes on four lupus patients who were treated with CYC during pregnancy. Two patients who were inadvertently exposed to CYC at conception for the treatment of lupus nephritis experienced spontaneous abortions in the first trimester. Two additional patients, treated with CYC at gestational weeks 20 and 22 for severe lupus flare, both suffered fetal demise within 7 days of introduction of cyclophosphamide, despite normal ultrasounds prior to treatment [109].

Cyclophosphamide should thus be avoided in early pregnancy. It should only be considered in severely ill women during the second half of pregnancy when all other options have been exhausted and the risk of pregnancy loss has been frankly discussed with the mother, although outcomes may still be poor for both the mother and fetus. Lactation is contraindicated during CYC use.

Mycophenolate mofetil (MMF) is a reversible inhibitor of inosine monophosphate that is being increasingly used for autoimmune conditions including lupus nephritis. MMF readily crosses the placenta. Exposure to MMF during embryogenesis leads to an increased rate of spontaneous abortions and an estimated 22–26 % rate of congenital malformations [110, 111]. A distinctive MMF embryopathy has been identified as the “EMFO tetrad: Ear (microtia and auditory canal atresia); Mouth (cleft lip and palate); Fingers (brachydactyly fifth fingers and hypoplastic toenails); and Organs (cardiac, renal, CNS, diaphragmatic and ocular)” [110]. Use of reliable contraception is mandatory for women of childbearing potential while taking MMF.

Women taking MMF who are planning pregnancy should discontinue the drug at a minimum of 6 weeks prior to conception [112]. In conditions where ongoing immunosuppression is required, azathioprine is a safer alternative. There are no data regarding the excretion of MMF into breast milk or its effect on the nursing infants. Therefore, lactation is also not recommended while using MMF.

Hydroxychloroquine (HCQ) is an antimalarial agent used for treatment of SLE and mild to moderate RA. The exact mechanism of action of HCQ is unknown; it is thought to interfere with antigen presentation and processing, thereby modulating the immune response. Its half-life is about 8 weeks; complete elimination of HCQ may take 6 months after discontinuation.

Hydroxychloroquine does cross the placenta. Over the years, data have accumulated in support of the safe use of HCQ (up to 400 mg daily) during human pregnancy [113]. Data from the Johns Hopkins Lupus Cohort showed no fetal or maternal risks associated with the continuation of HCQ throughout pregnancy [17]. No congenital malformations were demonstrated in a single placebo-controlled, randomized, double-blind study assessing the role of HCQ during pregnancy in SLE [114].

Furthermore, use of HCQ is associated with reduced development of congenital heart block (CHB) in children of mothers positive for anti-Ro/La antibodies [115]. Clowse et al. reported that among pregnant SLE patients, the risk for flare increases when HCQ use is discontinued, and higher doses of corticosteroids are needed to keep disease activity under control [17].

Hydroxychloroquine is secreted in breast milk at very low concentrations. No adverse effects have been observed in breastfed infants [116]. HCQ thus appears to be a safe option for use during conception, pregnancy, and lactation.

Sulfasalazine (SSZ) is a folic acid antagonist used for the treatment of rheumatoid arthritis (RA) and inflammatory bowel disease (IBD). The half-life of SSZ is between 5 and 10 h.

A meta-analysis of 2200 pregnant women with IBD, of which 642 women received sulfasalazine or related agents, found no statistically significant differences in congenital anomalies or other adverse pregnancy outcomes [117]. No increase in congenital malformations was found in exposed children in a registry-based Norwegian study [118].

A case was reported of congenital severe neutropenia in an infant whose mother was taking 3 g of SSZ daily throughout the pregnancy [119]. Thus, doses exceeding 2 g daily in pregnancy should be used cautiously.

There is a theoretical risk that sulfasalazine may cause folate deficiency since it inhibits dihydrofolate reductase and cellular uptake of folate [120]. As such, folate supplementation should probably be initiated before and throughout pregnancy. Furthermore, both SSZ and its metabolite sulfapyridine cross the placenta. A concern in late pregnancy is that sulfapyridine can displace bilirubin from albumin and lead to neonatal jaundice [121]. However, there are no reports of kernicterus occurring after in utero exposure to sulfasalazine.

Sulfapyridine is found in breast milk, at levels of approximately 30–60 % of the mother’s serum [122]. Exposure to sulfonamides through breast milk apparently does not pose a significant risk for the healthy, full-term newborn infant, but this risk should be considered in ill, stressed, jaundiced, or premature infants [116].

Azathioprine (AZA) has been used during pregnancy for management of solid organ transplantation, IBD, and rheumatic diseases. It is a prodrug that undergoes hepatic metabolism to 6-mercaptopurine (6-MP), its active metabolite. AZA and its metabolites are known to cross the placenta. The fetal liver lacks the enzyme inosinatopyrophosphorylase, which converts azathioprine to its active form. Therefore theoretically, the fetus is protected.

Azathioprine has a long track record of use in pregnancy with an acceptable safety profile. There was no significant increase in pregnancy complications or congenital malformations found in studies of pregnancies exposed to azathioprine for IBD or renal transplants [123–126], although there may be an increased risk of preterm labor and IUGR. These findings may reflect the severity of the underlying disease.

The AAP does not recommend breastfeeding while taking azathioprine because of the theoretical risk of immunosuppression. However, in women on azathioprine during lactation, mercaptopurine levels are undetectable, and no adverse events have been reported in breast-fed infants exposed to maternal azathioprine [127, 128].

The calcineurin inhibitors cyclosporine and tacrolimus prevent activation of T and B cells. More than 800 pregnancies exposed to cyclosporine and tacrolimus have been reported, mainly in transplant recipients, but also more sporadically in autoimmune disease [129]. Most of the studies of pregnancies exposed to the calcineurin inhibitors have found an increase in premature delivery and low birth weight, but no increase in congenital malformations [127, 130, 131]. It is not clarified whether the findings of prematurity and low birth weight are attributable to cyclosporine or to the underlying maternal disease.

Small amounts of cyclosporine are excreted in the breast milk. The AAP does not recommend breastfeeding while taking cyclosporine because of theoretical risks, but successful breastfeeding without adverse effects was reported in 15 children [132].

Corticosteroids are potent anti-inflammatory medications. These are considered safe during pregnancy, although there has been some concern that first trimester exposure is related to an increase in oral clefts [133]. A recent population-based study with 51,973 corticosteroid-exposed pregnancies did not find an increase in orofacial clefts regardless of type of corticosteroid administered (oral, inhalation, nasal spray, topical) [134]. Corticosteroids are classified as category B medications.

Betamethasone and dexamethasone are fluorinated steroids that are considerably less well metabolized by the placenta; they cross the placenta and have direct effects on the fetus. Most other corticosteroids (e.g., prednisone, prednisolone, and methylprednisolone) are metabolized in the placenta to inactivated forms. If the goal is to treat the mother, prednisone is the most ideal glucocorticoid because only a very small amount of active drug will enter the fetal circulation. Conversely, if the goal is to treat the fetus (such as for respiratory distress), betamethasone and dexamethasone are better options.

Prolonged corticosteroid use during pregnancy is associated with an increased risk of pregnancy-induced hypertension, preeclampsia, gestational diabetes, osteopenia, and infections, especially at doses of above 20 mg/day.

Corticosteroids are secreted in the breast milk at low concentrations and are considered safe to use during breastfeeding, especially at doses less than 20 mg prednisone daily (or the equivalent) [135].

The “Biologics,” or biologic DMARDs, are biologically engineered molecules designed to target and inhibit specific molecules associated with the initiation and maintenance of inflammation. Biologics have been designed to target a variety of pro-inflammatory cytokines (e.g., tumor necrosis factor [TNF]), as well as B-cell receptors and T-cell co-stimulatory molecules. Many of these are effective in controlling inflammation and in preventing joint damage and destruction. Some, like the TNF inhibitors, are consistently accumulating data to support their safety in pregnancy. Others, like abatacept and tocilizumab, have too little data at this point to recommend their use during most pregnancies.