Michelle Y. Owens

Posterior reversible encephalopathy syndrome in 46 of 47 patients with eclampsia.

OBJECTIVE We sought to investigate the concurrence of posterior reversible encephalopathy syndrome (PRES) with eclampsia and to describe the obstetric, radiological, and critical care correlates. STUDY DESIGN This was a single-center, 2001-2010 retrospective cohort study of all patients with eclampsia who underwent neuroimaging via magnetic resonance imaging (MRI) or computerized tomography (CT) with or without contrast. RESULTS Forty-six of 47 of eclamptic patients (97.9%) revealed PRES on neuroimaging using 1 or more modalities: MRI without contrast, 41 (87.2%); MRI with contrast, 27 (57.4%); CT without contrast, 16 (34%); CT with contrast, 7 (14.8%); and/or magnetic resonance angiography/magnetic resonance venography, 2 (4.3%). PRES was identified within the parietal, occipital, frontal, temporal, and basal ganglia/brainstem/cerebellum areas of the brain. Eclampsia occurred antepartum in 23 patients and postpartum in 24 patients. Headache was the most common presenting symptom (87.2%) followed by altered mental status (51.1%), visual disturbances (34%), and nausea/vomiting (19.1%). Severe systolic hypertension was present in 22 patients (47%). CONCLUSION The common finding of PRES in patients with eclampsia suggests that PRES is a core component of the pathogenesis of eclampsia. Therapy targeted at prevention or reversal of PRES pathogenesis may prevent or facilitate recovery from eclampsia.

Standardized Mississippi Protocol Treatment of 190 Patients with HELLP Syndrome: Slowing Disease Progression and Preventing New Major Maternal Morbidity

Objective. To evaluate the effectiveness of the Mississippi Protocol (MP) to treat HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome. Methods. Uniform early initiation of MP (corticosteroids, magnesium sulfate, systolic blood pressure control) was studied prospectively in patients admitted with severe preeclampsia/class 1 or class 2 HELLP syndrome. Results. One hundred and ninety patients between 2000 and 2007 received MP without suffering maternal death, stroke, or liver rupture. Only 39 of 163 patients (24%) not class 1 when MP began progressed to class 1 disease; only 18.2% of class 1 and 2.4% of class 2 subsequently developed major maternal morbidity. Conclusion. Early initiation of MP inhibits HELLP syndrome disease progression and severity.

Hypertension in response to CD4+ T cells from reduced uterine perfusion pregnant rats is associated with activation of the endothelin-1 system

We have shown that adoptive transfer of CD4(+) T cells from placental ischemia (reduction in uteroplacental perfusion, RUPP) rats causes hypertension and elevated inflammatory cytokines during pregnancy. In this study we tested the hypothesis that adoptive transfer of RUPP CD4(+) T cells was associated with endothelin-1 activation as a mechanism to increase blood pressure during pregnancy. CD4(+) T cells from RUPP or normal pregnant (NP) rats were adoptively transferred into NP rats on gestational day 13. Mean arterial pressure (MAP) was analyzed on gestational day 19, and tissues were collected for endothelin-1 analysis. MAP increased in placental ischemic RUPP rats versus NP rats (124.1 ± 3 vs. 96.2 ± 3 mmHg; P = 0.0001) and increased in NP recipients of RUPP CD4(+) T cells (117.8 ± 2 mmHg; P = 0.001 compared with NP). Adoptive transfer of RUPP CD4(+) T cells increased placental preproendothelin-1 mRNA 2.1-fold compared with NP CD4(+) T cell rats and 1.7-fold compared with NP. Endothelin-1 secretion from endothelial cells exposed to NP rat serum was 52.2 ± 1.9 pg·mg(-1)·ml(-1), 77.5 ± 4.3 pg·mg(-1)·ml(-1) with RUPP rat serum (P = 0.0003); 47.2 ± .16 pg·mg(-1)·ml(-1) with NP+NP CD4(+) T cell serum, and 62.2 ± 2.1 pg·mg(-1)·ml(-1) with NP+RUPP CD4(+) T cell serum (P = 0.002). To test the role of endothelin-1 in RUPP CD4(+) T cell-induced hypertension, pregnant rats were treated with an endothelin A (ET(A)) receptor antagonist (ABT-627, 5 mg/kg) via drinking water. MAP was 92 ± 2 mmHg in NP+ET(A) blockade and 108 ± 3 mmHg in RUPP+ET(A) blockade; 95 ± 5 mmHg in NP+NP CD4(+) T cells+ET(A) blockade and 102 ± 2 mmHg in NP+RUPP CD4(+) T cells+ET(A) blockade. These data indicate the importance of endothelin-1 activation to cause hypertension via chronic exposure to activated CD4(+) T cells in response to placental ischemia.

A high LDH to AST ratio helps to differentiate pregnancy-associated thrombotic thrombocytopenic purpura (TTP) from HELLP syndrome

Objective: Differentiating between pre-eclampsia/HELLP syndrome and pregnancy-associated thrombotic thrombocytopenic purpura (TTP) is difficult but important in order to undertake timely and potentially life-saving plasma exchange (PEX) therapy for TTP recovery. We review our institutional experience with pregnancy-associated TTP and determine if the ratio of LDH to AST reliably distinguishes patients with TTP from those with HELLP syndrome. Study design: This is a retrospective case control study of all pregnant/puerperal patients with TTP from a single tertiary care center during 1986–2006. Laboratory findings in patients with TTP were compared to patients who met all criteria for class 1 or 2 HELLP syndrome within the first 24 hours of hospital admission during 2000–2007. Results: Thirteen pregnant (n = 10) or puerperal (n = 3) patients with TTP were identified; 11 cases were primary, 2 were recurrent. TTP laboratory findings included LDH to AST ratios of 77 ± 42.17; Patients with HELLP syndrome (N = 83) had significantly lower LDH to AST ratios of 20.04 ± 2.13. Based on an ROC analysis, an LDH/AST ratio ≥22.12 discriminates well between TTP and antenatal HELLP subjects (AUC = 0.99). Conclusion: A high LDH to AST ratio >22.12 suggests that TTP is a more likely diagnosis than HELLP syndrome in the third trimester pregnant patient, presenting with findings that could be compatible with either diagnosis. In these circumstances, it is advisable to obtain hematology consultation and to consider PEX implementation.

Hyperuricemia facilitates the prediction of maternal and perinatal adverse outcome in patients with severe/superimposed preeclampsia.

Objective. Hyperuricemia has received much attention and debate recently with regard to its utility as a marker for preeclampsia and as a predictor of adverse maternal–fetal outcome. This investigation was undertaken in patients with severe/superimposed preeclampsia to determine whether the maternal uric acid (UA) level at initial hospital admission is a useful predictor of subsequent adverse maternal and/or perinatal outcomes. Methods. Retrospective analysis of all patients diagnosed with severe preeclampsia, superimposed preeclampsia or HELLP syndrome during 2005 at the University of Mississippi Medical Center (UMMC). Clinical and laboratory data were collected, entered and stored electronically in a password protected, secure system. Results. Adverse maternal outcomes occurred in 15.3% of 258 patients in the cohort. Mean UA concentration in the absence of adverse maternal outcomes was 342.6 ± 77.3 compared to 396.1 ± 117.2 μmol/l in pregnancies with complications (p < 0.001). The positive likelihood ratio (LR) for adverse maternal outcome was 5.3 with UA ≥ 76.3 μmol/l and creatinine ≥1.0 mg/dl. LRs rose in association with other abnormal preeclampsia serum markers. Adverse perinatal outcomes occurred in 45.2% of births. The LRs for adverse perinatal outcomes remained unchanged around 1.0. Mean UA was 363.4 ± 91.0 compared to 339.0 ± 80.9 μmol/l in pregnancies without adverse outcomes (p = 0.021). Conclusions. Maternal hyperuricemia is a better predictor of maternal than perinatal risk and adverse outcome.

HELLP Syndrome with and without Eclampsia

We assessed pregnancy outcomes for patients with HELLP syndrome (hemolysis; elevated liver enzymes; low platelet count) with and without concurrent eclampsia. We performed a retrospective investigation of data spanning three decades of patients with class 1 or 2 HELLP syndrome with concurrent eclampsia (HELLP + E) and patients with HELLP syndrome without eclampsia. Data were analyzed by appropriate tests for continuous or categorical outcomes with differences considered significant if P < 0.05. During 1981 to 1996 and 2000 to 2006, there were 693 patients with class 1 or 2 HELLP syndrome; altogether, 70 patients had HELLP + E. The only demographic difference was greater nulliparity in HELLP + E patients. Otherwise, inconsistent and clinically insignificant differences were observed between groups. Despite the relatively large size of the study groups, we were unable to detect a significant worsening of maternal or perinatal outcome in HELLP + E patients compared with HELLP patients. In our experience, eclampsia does not appear to contribute a significant adverse impact upon the course or outcome of HELLP syndrome pregnancies.

Seeking the mechanism(s) of action for corticosteroids in HELLP syndrome: SMASH study

INTRODUCTION Administration of dexamethasone to the hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome patients (10 mg intravenously [IV] every 12 hours) shortens the disease course and reduces maternal morbidity in patients treated at the University of Mississippi Medical Center (UMMC), associated with this severe form of preeclampsia. However, the pathophysiological mechanisms involved with this intervention remain unclear. OBJECTIVE We sought to investigate the potential role of IV dexamethasone to restore the imbalance among antiangiogenic and inflammatory factors known to be significantly elevated in women with HELLP syndrome. STUDY DESIGN This was a single-center prospective study of women diagnosed with HELLP syndrome who were treated for IV dexamethasone at UMMC. Blood was drawn prior to dexamethasone administration and again 12 and 24 hours after the initial dexamethasone administration. Enzyme-linked immune assays were used to measure circulating inflammatory cytokines and antiangiogenic factors. A repeated-measures analysis of variance was used to analyze the data collected before, after, and during dexamethasone administration. RESULTS Seventeen women with HELLP syndrome were enrolled in this study. Dexamethasone significantly decreased evidence of hemolysis (P = .002) and liver enzymes (P = .003), and significantly increased platelets (P = .0001) within 24 hours of administration. Circulating interleukin-6 levels after 24 hours were decreased (P < .001); soluble fms-like tyrosine kinase-1 and soluble endoglin were also significantly decreased by 24 hours after dexamethasone administration (P < .002 and P < .004, respectively). There were no significant differences in circulating levels of placental growth factor (P = .886) due to dexamethasone administration. Angiotensin II receptor autoantibody levels were unchanged by dexamethasone administration. CONCLUSION We conclude that 1 important mechanism of dexamethasone administration is to blunt the release of both antiangiogenic and inflammatory factors suggested to play role in the pathophysiology of HELLP syndrome.

Postpartum thrombotic microangiopathic syndrome.

OBJECTIVE Characterization of syndromes for patients with life-threatening, progressively worsening hemolysis-elevated-liver-enzymes-and-platelet (HELLP) syndrome-like diseases and with thrombotic microangiopathies. RETROSPECTIVE STUDY DESIGN: Patients who underwent postpartum plasma-exchange (PPEX) for preeclampsia-related, and microangiopathy/coagulopathy illnesses unresponsive to medical therapy between 1994 and 2008 in our center and elsewhere. RESULTS Nine patients were treated with PPEX in our center with 78% maternal survival. Treatment with PPEX increased platelet levels (p=0.048), decreased serum lactic dehydrogenase (p=0.0012) and aspartate aminotransferase (p=0.0001). CONCLUSION Nineteen patients from publications combined with our patients suggest five categories of postpartum thrombotic microangiopathy syndrome that exhibit HELLP syndrome criteria and respond to PPEX.

Hellp syndrome and composite major maternal morbidity: importance of Mississippi classification system

Abstract Objective: We explored the prevalence of Composite Major Maternal Morbidity (CMMM) for patients with severe preeclampsia (SPRE) and each class or category of HELLP syndrome. Methods: In a retrospective cohort study from 2000 to 2010, we reviewed maternal charts of patients categorized with complete or partial HELLP syndrome. From 2005 to 2007, the maternal charts for every patient with a diagnosis of SPRE without HELLP syndrome were also evaluated for comparison. The CMMM for each patient group included cardiopulmonary; hematologic/coagulation, central nervous system/visual, hepatic or renal complications. During the study interval patients with class 1 and class 2 HELLP syndrome received Mississippi Protocol management. Results: Four hundred and ninety-five mothers had a form of HELLP syndrome in years 2000–2010; 688 mothers experienced a non-HELLP severe form of preeclampsia during 2005–2007. The prevalence of CMMM for each patient group was: class 1 = 44%; class 2 = 13%; class 3 = 24%; partial HELLP = 20% and SPRE = 18%. CMMM for class 1 HELLP syndrome is significantly higher than all other groups (p < 0.001). Conclusions: Patients who develop class 1 HELLP syndrome have significantly higher CMMM. Avoiding this most advanced stage of HELLP syndrome and minimizing the development of new MMM becomes a measure of medical management effectiveness and a tool to assess overall quality of care.

Hypertension in an Animal Model of HELLP Syndrome is Associated With Activation of Endothelin 1

Women with hypertensive forms of pregnancy such as hemolysis–elevated liver enzymes–low platelet syndrome have increased circulating endothelin 1; however, the relationship between hypertension and endothelin 1 has not been studied. Using an animal model, we sought to determine whether there was an increased activation/dysfunction of endothelin 1, the effect of endothelin 1 receptor-A blockade on hypertension and other manifestations of hemolysis, elevated liver enzymes, and low platelets syndrome. On gestational day 12, timed-pregnant rats were infused with soluble fms-like tyrosine kinase 1 (sFlt-1) and soluble endoglin (sEndoglin; 4.7 and 7 µg/kg) via mini-osmotic pumps for 8 days. A subset of rats were treated with receptor-A antagonist (ABT-627, 5mg/kg) for 8 days. Rats with hemolysis-elevated liver enzymes-low platelet syndrome had significantly increased hypertension (P = .0001), circulating endothelin 1 (P = .03), and a significant 3.3- and 7.2-fold increase in preproendothelin messenger RNA (mRNA) expression in the placenta and liver (P = .01 and .04). Urinary protein:creatinine ratio was significantly increased in these animals (P = .0007), and circulating factors from these rats stimulated a significant increase in endothelial cell secretion of endothelin 1 (P = .001) in an in vitro assay. Blockade of the endothelin 1 receptor A significantly decreased hypertension (P = .001), circulating endothelin 1, and interleukin 17 (P = .004 and .003), placental preproendothelin mRNA expression (P = .016), and urinary protein:creatinine ratio (P = .007) in rats with hemolysis–elevated liver enzymes–low platelet syndrome. Blockade of the endothelin 1 receptor A significantly decreased hemolysis (P = .009), liver enzymes (P = .011), and significantly increased platelet levels (P = .03) and decreased circulating CD4+ and CD8+ T lymphocytes (P = .0004 and .0001) in rats infused with sFlt-1 and sEndoglin. These data support the hypothesis that endothelin 1 activation has a critical role in pathophysiology of as hemolysis–elevated liver enzymes–low platelet syndrome.