Placental SLE like Autoimmunity and Fetal Loss

UoM administered thesis: Phd

  • Authors:
  • Hannah Kither

Abstract

Introduction: Systemic Lupus Erythematosus (SLE) is a multisystem autoimmune disease of significant female preponderance. It is associated with increased rates of adverse pregnancy outcomes (APOs), including stillbirth. The relationship between SLE and stillbirth is bidirectional, with women who have had a stillbirth at increased risk of developing SLE. The underlying cause of pregnancy pathologies with SLE has not been fully established, but aberrant placental formation and/or maternal maladaptation to pregnancy, at an immune or vascular level, are plausible. This thesis sought to explore the relationship between stillbirth and SLE in pregnancy, with the hypothesis that women who have a stillbirth display similar vascular and maternal immune issues. Methods: A multi-method approach was taken to address this research question, involving both epidemiological and prospective studies. A large scale epidemiological study was undertaken utilising a UK national primary care database (Clinical Practice Research Datalink, CPRD) to ascertain the risk of developing SLE, following an APO. In the prospective studies, three pregnant cohorts were considered: (i) those with SLE, (SLE Pregnant (SP), n=51), (ii) prior stillbirth (Previous Loss (PL), n=29) or (iii) uncomplicated pregnancies (Normal Pregnant (NP, n=44). Maternal vascular changes were assessed by brachial blood pressure (BP), photoplethysmography (stiffness index (SI), and reflection index (RI)), arteriography (pulsewave velocity (PWV)), plasma placental growth factor (PlGF) and soluble FMS-like tyrosine-kinase 1 (sFLT-1), and uterine artery Doppler velocimetry (UtAD). Immune changes were monitored by peripheral blood microparticles (MPs), T helper 17 (Th17) and T regulatory (Treg) cell numbers. Placental assessments of in utero placental biometry were undertaken, along with placental histological examination and complement deposition (complement factor 4d (C4d) and complement factor 3a receptor (C3aR)). A retrospective study of stillbirth placentas was also conducted. Results: The UK epidemiological study identified 20,123 cases of APO and 97,323 livebirths. The overall incidence of SLE was 0.05%. Women with a stillbirth had a relative risk (RR) of developing SLE of 4.10 (95% CI 3.14-5.36)) compared to livebirth outcomes. In the prospective study, the SP group had the lowest gestation at delivery, exaggerated by lupus nephritis. In utero, placental widths were smallest in the SP group and largest in NP. No difference in C4d staining was defined in livebirth placentas, although stillbirth cohorts had exaggerated deposition associated with villitis (V) and maternal vascular malperfusion (MVM). C3aR was also highest in NP and lowest in the SP group. In stillbirth cases, C3aR deposition was higher in those associated with MVM. Mean arterial BP was higher in PL and lower in NP across gestation. No drop in second trimester BP was seen in PL cases in their current pregnancy. PWV increased with gestation and was highest in SP at 17-28 weeks’ gestation. UtAD measures fell with increasing gestation. In SP, the presence of abnormal UtAD was associated with lower gestation at delivery. PlGF fell with increasing gestation and was lowest in SP, whilst sFLT-1 was raised. 21% of PL patients displayed seropositive autoantibodies, with concomitant elevation in Th17 cells. No differences in Treg cells were defined, but total MPs were higher in PL, over SP and NP groups. Conclusions: UK women with a prior stillbirth have increased lifelong risk of developing SLE. They demonstrate similarities (vascular and immunological) to women with confirmed SLE diagnosis. Their immunological changes in maternal autoantibodies, placental histology and complement deposition suggest pathological similarities to SLE, with possible targets for therapeutic intervention.

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Original languageEnglish
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Award date1 Aug 2019