Rheumatologists are increasingly involved in the care of young women who, in the age of biologic therapy, are now gaining control of their rheumatic diseases and attempting pregnancy. With careful planning, most women with rheumatic diseases have successful pregnancies. This article focuses specifically on the highest-risk pregnancies and controversial areas. We discuss the women at risk of complications, the types of maternal and fetal complications, the treatments that can be used in pregnancy (and breastfeeding) and longer-term outcomes that could affect the mother. SLE, RA, ANCA-associated vasculitides, large vessel vasculitis (e.g. Takayasu's) and other CTDs (e.g. scleroderma) are among the conditions covered. The evidence and controversies regarding the recommendations for the use of biologics in pregnancy are discussed. The role of the rheumatologist in pregnancy planning and caring for the pregnant and post-partum woman as part of the multidisciplinary team is discussed.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• The prodrug cyclophosphamide requires bioactivation by liver CYP enzymes.• Controversy exists about which CYP isoforms are important in the in vitro bioactivation of this drug.• Recent clinical studies have highlighted a role for either CYP2C19 or CYP2B6 in the therapeutic response to cyclophosphamide in lupus patients. • However, the role of these isoforms in the bioactivation of cyclophosphamide in lupus patients has not been previously demonstrated. WHAT THIS STUDY ADDS• Low bioactivation of cyclophosphamide by human liver appears to be dependent on a combination of both CYP2C19 and CYP2B6 loss of function variants.• In a preliminary study of lupus patients poor bioactivation of cyclophosphamide was also observed in those individuals who had at least one loss of function allele at either CYP2C19 or CYP2B6. AIMSThe role of CYP pharmacogenetics in the bioactivation of cyclophosphamide is still controversial. Recent clinical studies have suggested a role for either CYP2C19 or CYP2B6. The aim of this study was to clarify the role of these pharmacogenes. METHODSWe used a combined in vitro-in vivo approach to determine the role of these pharmacogenes in the bioactivation of the prodrug to 4-hydroxy cyclophosphamide (4-OHCP). Cyclophosphamide metabolism was determined in a human liver biobank (n = 14) and in patients receiving the drug for treatment of lupus nephritis (n = 16) RESULTSIn livers of known CYP2C19 and CYP2B6 genotype and protein expression we observed that there was a combined role for both CYP2C19 and CYP2B6 in the bioactivation of cyclophosphamide in vitro. The presence of at least one loss of function (LoF) allele at either CYP2C19 or CYP2B6 resulted in a significant decrease in both Vmax (P = 0.028) and CLint (P = 0.0017) compared with livers with no LoF alleles. This dual genotype relationship was also observed in a preliminary clinical study, with patients who had Ն1 LoF allele at either CYP2C19 or CYP2B6 also displaying significantly (P = 0.0316) lower bioactivation of cyclophosphamide. The mean 4-OHCP : CP bioactivation ratio was 0.0014 (95% CI 0.0007, 0.002) compared with 0.0071 (95% CI 0.0001, 0.014) in patients with no LoF alleles at either of these genes. CONCLUSIONSThe presence of Ն1 LoF allele(s) at either CYP2B6 or CYP2C19 appeared to result in decreased bioactivation of cyclophosphamide both in vitro and in patients. Further clinical studies to confirm this relationship are warranted.

Systemic lupus erythematosis (SLE) commonly affects women of child bearing-age, and advances in treatment have resulted in an increasing number of women with renal involvement becoming pregnant. Knowledge of the relationship of the condition with respect to fertility and pregnancy is important for all clinicians involved in the care of women with lupus nephritis because they have complicated pregnancies. Presentation of lupus nephritis can range from mild asymptomatic proteinuria to rapidly progressive renal failure and may occur before, during, or after pregnancy. The timing of diagnosis may influence pregnancy outcome. Pregnancy may also affect the course of lupus nephritis. All pregnancies in women with lupus nephritis should be planned, preferably after more than six-months of quiescent disease. Predictors of poor obstetric outcome include active disease at conception or early pregnancy, baseline poor renal function with Creatinine >100 μmol/L, proteinuria >0.5 g/24 hours, presence of concurrent antiphospholipid syndrome and hypertension. In this review the most recent studies of pregnancies in women with lupus nephritis are discussed and a practical approach to managing women prepregnancy, during pregnancy and post-partum is described.