ABSTRACT
BACKGROUND: One approach to decreasing the cesarean birth rate in the United States is to increase the availability of birth attendants, including certified nurse-midwives (CNMs), who offer trial of labor after cesarean (TOLAC). We examined associations between provider type and mode of birth for women attempting vaginal birth after cesarean (VBAC). METHODS: We performed a retrospective cohort study at a United States academic medical center using prospectively-collected data (2005-2012). We included healthy women with term singleton vertex pregnancies after one or two prior cesareans who were managed by obstetricians or CNMs. We assessed unplanned cesarean birth by provider type using univariate and logistic regression and examined labor interventions and predicted VBAC success. RESULTS: Overall VBAC success was 88% for 502 included patients. Unplanned cesarean rates were similar by provider type. Black race, no prior VBAC, recurring clinical indication for cesarean, labor augmentation/induction, and any Pitocin use were associated with increased unplanned cesarean. Higher parity and early-term gestational age at delivery were associated with decreased unplanned cesarean. Postpartum hemorrhage and composite maternal morbidity were increased with unplanned cesarean, but there was no difference in neonatal outcome by mode of delivery or provider type. Obstetricians had slightly higher composite adverse maternal outcomes. Nomogram-predicted VBAC success but not provider type was associated with unplanned cesarean. CONCLUSIONS: Unplanned cesarean was similar for patients attempting labor after cesarean managed by midwives or obstetricians. Increasing the number of CNMs who manage TOLAC may help decrease the high rate of cesareans.
Subject(s)
Oxytocics/therapeutic use , Oxytocin/therapeutic use , Postpartum Hemorrhage/etiology , Trial of Labor , Vaginal Birth after Cesarean/statistics & numerical data , Adolescent , Adult , Colorado , Female , Gestational Age , Humans , Labor Onset , Logistic Models , Parity , Postpartum Hemorrhage/epidemiology , Pregnancy , Retrospective Studies , Tertiary Care Centers , Vaginal Birth after Cesarean/adverse effects , Young AdultABSTRACT
Although B cells have emerged as important contributors to chronic graft-versus-host-disease (cGVHD) pathogenesis, the mechanisms responsible for their sustained activation remain unknown. We previously showed that patients with cGVHD have significantly increased B cell-activating factor (BAFF) levels and that their B cells are activated and resistant to apoptosis. Exogenous BAFF confers a state of immediate responsiveness to antigen stimulation in normal murine B cells. To address this in cGVHD, we studied B-cell receptor (BCR) responsiveness in 48 patients who were >1 year out from allogeneic hematopoietic stem cell transplantation (HSCT). We found that B cells from cGVHD patients had significantly increased proliferative responses to BCR stimulation along with elevated basal levels of the proximal BCR signaling components B cell linker protein (BLNK) and Syk. After initiation of BCR signaling, cGVHD B cells exhibited increased BLNK and Syk phosphorylation compared with B cells from patients without cGVHD. Blocking Syk kinase activity prevented relative post-HSCT BCR hyper-responsiveness of cGVHD B cells. These data suggest that a lowered BCR signaling threshold in cGVHD associates with increased B-cell proliferation and activation in response to antigen. We reveal a mechanism underpinning aberrant B-cell activation in cGVHD and suggest that therapeutic inhibition of the involved kinases may benefit these patients.
Subject(s)
B-Lymphocytes/metabolism , Graft vs Host Disease/immunology , Graft vs Host Disease/metabolism , Receptors, Antigen, B-Cell/physiology , Adult , Aged , B-Cell Activating Factor/metabolism , B-Lymphocytes/pathology , Cell Proliferation , Cells, Cultured , Chronic Disease , Female , Humans , Lymphocyte Activation/physiology , Male , Middle Aged , Primary Cell Culture , Receptors, Antigen, B-Cell/agonists , Young AdultABSTRACT
Recent data reveal an important role for B cells in the pathogenesis of chronic GVHD (cGVHD). Patients with cGVHD have delayed B-cell reconstitution and elevated BAFF to B-cell ratios compared to patients without cGVHD. The mechanisms promoting and sustaining B-cell activation in this disease, however, remain unknown. As BAFF increases murine B-cell metabolism and survival and maintains autoreactive B-cell clones, we performed ex vivo analyses of peripheral B cells from 51 patients who either had or did not have active cGVHD and were greater than 1 year from the time of allogeneic hematopoietic stem cell transplantation. We found that B cells from patients with active cGVHD were in a heightened metabolic state and were resistant to apoptosis. Exogenous BAFF treatment amplified cell size and survival in B cells from these patients. We found significantly increased signaling through ERK and AKT that associated with decreased levels of proapoptotic Bim, suggesting a mechanistic link between elevated BAFF levels and aberrant B-cell survival. Thus, we identify a role for BAFF in the pathogenesis of cGVHD and define B-cell activation and survival pathways suitable for novel therapeutic development in cGVHD.