*8.4.4 Leflunomide*

Leflunomide (LEF) is another drug that, although it may not be teratogenic, it is strongly advised to be avoided during pregnancy [68, 69]. It's an antimetabolite that inhibits dihydroorotate dehydrogenase, the catalyst enzyme responsible for the limiting step in pyrimidine biosynthesis. Despite its short half-life (approximately 15 days), its major metabolite follows a long path through enterohepatic circulation remaining detectable for more than 2 years. It is essential to complete its washout until undetectable levels before switching to alternative medication compatible with pregnancy and trying to conceive. For accelerate elimination of this drug, for example if an accidental pregnancy occurs, it is used cholestyramine (8 g orally, 3 times a day, for 11 days).

## **8.5 Management of maternal antiphospholipid syndrome**

APL carriers or APS pregnancy represent a great challenge and require an additional monitoring and therapy to prevent maternal and/or fetal complications. Below is the clinical management according to the different clinical situations: [23, 52]

## *8.5.1 Asymptomatic aPL-positive patients "aPL carriers"*

In SLE *aPL carriers* prophylaxis with LDA daily, is recommended during pregnancy. Combination therapy with prophylactic-dose heparin and LDA, even for those pregnant with triple-positive aPL or high LAC concentration, is not recommended [23, 52]. These women should be treated with prophylactic-dose low molecular weight heparin (LMWH) until, at least, 6 weeks after delivery.

## *8.5.2 Obstetric APS*

In SLE women with history of obstetric complications prophylactic or therapeutic-dose heparin (usually LMWH) and LDA during gestation is recommended. Prophylactic or therapeutic-dose LMWH should continue until 6 weeks after delivery [23, 52].

#### *8.5.3 Thrombotic APS*

Women with previous thrombosis have a high risk of recurrent thrombotic event during pregnancy. Therefore, as soon as pregnancy is confirmed, vitamin K antagonists should be stopped, due to the fetotoxicity, and should be switched to therapeutic LMWH and LDA). LMWH and LDA should be stopped before delivery. Women with thrombotic APS are at very high risk of recurrent venous thromboembolism during post-partum. Therapeutic LMWH dose is recommended. Other possible option is to return to warfarin, which is safe during breastfeeding [23].

#### *8.5.4 Refractory obstetric APS*

Refractory Obstetric APS is a delicate and challenging situation, as there is no response to standard therapy. Some alternatives can be tried such as increased-dose of heparin (LMWH), low-dose prednisone (10 mg/day in the 1st trimester), IVIG, plasmapheresis, HCQ (5-6 mg/Kg/day). In 25% of obstetric APS, despite treatment, pregnancy loss can occur [23].
