Background/Purpose:   Systemic lupus erythematosus (SLE) is associated with increased risk of adverse pregnancy outcomes (APO), including preeclampsia and intrauterine growth restriction.  While significant placental pathology is expected in patients with preeclampsia, less is known about how lupus disease activity during pregnancy affects the placenta.  Here, we describe a lupus population in which disease control was generally excellent during pregnancy, and in which only 30% of the pregnancies were complicated by preeclampsia.  In addition to standard pathologic review, we also specifically quantified neutrophils and neutrophil extracellular traps (NETs) given their recognized association with preeclampsia in the general population, as well as endothelial damage in SLE.

Methods:   Preeclampsia, SLE, and healthy placentas were scored for typical histologic features including inflammation, hemorrhage, and infarction.  Neutrophils were quantified with the aid of immunohistochemical staining for the granular protein myeloperoxidase.  NETs were identified by extracellular myeloperoxidase staining in the setting of decondensed nuclei.  Nonparametric analysis was used to evaluate differences in netting and intact neutrophils between groups.  Logistic regression was used to identify associations between histology and neutrophils.

Results:   Placentas from 11 preeclampsia, 4 SLE+preeclampsia, 10 SLE pregnancies (no preeclampsia), and 10 healthy/control pregnancies were evaluated.  Lupus disease activity during pregnancy was low in all but one patient.  Surprisingly, as compared to controls, significantly more NETs were found infiltrating not justpreeclampsia (p=0.0003) and SLE+preeclampsia (p=0.0345) placental intervillous spaces, but also all 10 of the SLE non-preeclampsia cases (p=0.0019).  The ratio of NETs to total neutrophils was also increased in all three groups (p=0.0015, p=0.0345, p=0.0019, respectively, as compared to controls).  The presence of NETs was further associated with striking histologic abnormalities including severe vasculitis with fibrinoid necrosis (p=0.02286), acute and chronic hemorrhage (p=0.02116), and laminar decidual necrosis (p=0.03458) in all groups.  In summary, the placentas of clinically-stable SLE pregnancies were markedly inflamed and essentially indistinguishable from preeclampsia placentas.

Conclusion:   Preeclampsia, SLE+preeclampsia, and clinically-stable SLE pregnancies were all associated with significantly higher numbers of intervillous NETs, and greater ratios of netting to total neutrophils as compared to controls.  This was true not just for preeclampsia placentas, but also for placentas of lupus patients whose disease activity was low during pregnancy (and who did not have clinical preeclampsia).  In summary, these data suggest lupus and preeclampsia pregnancies may share common pathogenesis that is elaborated in lupus despite clinically quiescent disease.  Future studies of lupus pregnancies are required to elucidate mechanisms of this abnormal placentation, as it may have implications for both APOs and long-term outcomes of children born to mothers with SLE.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/placentas-of-lupus-pregnancies-are-characterized-by-marked-inflammatory-changes-despite-good-disease-control/