Pregnancy-associated hemolytic uremic syndrome revisited in the era of complement gene mutations

Abstract

In contrast to pregnancy-associated thrombotic thrombocytopenic purpura, the pathogenesis and presentation of pregnancy-associated atypical hemolytic uremic syndrome (P-aHUS) remain ill-defined. We conducted a retrospective study to assess the presentation and outcomes of patients presenting with P-aHUS and the prevalence of alternative C3 convertase dysregulation. P-aHUS occurred in 21 of the 100 adult female patients with atypical HUS, with 79% presenting postpartum. We detected complement abnormalities in 18 of the 21 patients. The outcomes were poor: 62% reached ESRD by 1 month and 76% by last follow-up. The risk for P-aHUS was highest during a second pregnancy. Thirty-five women, 26 (74%) of whom had complement abnormalities, had at least one pregnancy before the onset of a non-pregnancy-related aHUS. Outcomes did not differ between patients with pregnancy-related and non-pregnancy-related aHUS. Mutations in the SCR19-20 domains of factor H were less frequent in P-aHUS patients compared with non-pregnancy-related aHUS. Pregnancies in female patients with complement abnormalities (n = 44) were complicated by fetal loss and preeclampsia in 4.8% and 7.7%, respectively. Better understanding of complement dysregulation in pregnancy complications is essential, especially to guide development of pharmacologic agents to modulate this system.

Figure 1.

Risk of aHUS in patients with documented complement dysregulation is highest during the second pregnancy.

Figure 2.

CFH mutations in female patients with aHUS are located mainly outside the SCR19-20 domains. Three patients have two mutations: CFH/C3, CFH/MCP, and CFH/CFH.

Figure 3.

Complement dysregulation-associated aHUS in the French cohort (18 patients) occurs mainly in the postpartum, whereas ADAMTS13 deficiency-associated TTP (23 previously published cases)^– occurs mainly during pregnancy.