Sharon Keiser

Thrombotic thrombocytopenic purpura in 166 pregnancies: 1955-2006

A review of pregnancy-associated thrombotic thrombocytopenic purpura (TTP) in 166 pregnancies was undertaken using 92 English-language publications from 1955 to 2006. Initial and recurrent TTP presents most often in the second trimester (55.5%) after 1-2 days of signs/symptoms; postpartum TTP usually occurs following term delivery. TTP with preeclampsia (n = 28) exhibits 2-4 times higher aspartate aminotransferase (AST) values and lower total lactate dehydrogenase (LDH) to AST ratios (LDH to AST ratio = 13:1), compared with TTP without preeclampsia (LDH to AST ratio = 29:1). Maternal mortality is higher with initial TTP (26% vs 10.7%), especially with concurrent preeclampsia (44.4% vs 21.8%, P < .02). Although maternal mortality with TTP has substantially declined when plasma therapy is utilized, delay of diagnosis and therapy for initial TTP confounded by preeclampsia/hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome remains a significant maternal-perinatal threat. Rapid and readily available laboratory testing to quickly diagnose TTP and HELLP syndrome/preeclampsia is desperately needed to improve care.

The effect of immune factors, tumor necrosis factor-alpha, and agonistic autoantibodies to the angiotensin II type I receptor on soluble fms-like tyrosine-1 and soluble endoglin production in response to hypertension during pregnancy.

BACKGROUND Preeclampsia is considered a disease of immunological origin associated with abnormalities in inflammatory cytokines, tumor necrosis factor-alpha (TNF-alpha), and activated lymphocytes secreting autoantibodies to the angiotensin II receptor (AT1-AA). Recent studies have also demonstrated that an imbalance of angiogenic factors, soluble fms-like tyrosine kinase (sFlt-1), and sEndoglin, exists in preeclampsia; however, the mechanisms that initiate their overproduction are unclear. METHODS To determine the role of immune regulation of these factors, circulating and placental sFlt-1 and/or sEndoglin was examined from pregnant rats chronically treated with TNF-alpha or AT1-AA. On day 19 of gestation blood pressure was analyzed and serum and tissues were collected. Placental villous explants were excised and cultured on matrigel coated inserts for 24 h and sFlt-1 and sEndoglin was measured from media. RESULTS In response to TNF-alpha-induced hypertension, sFlt-1 increased from 180 +/- 5 to 2,907 +/- 412 pg/ml. sFlt-1 was also increased from cultured placental explants of TNF-alpha induced hypertensive pregnant rats (n = 12) (2,544 +/- 1,132 pg/ml) vs. explants from normal pregnant (NP) rats (n = 12) (2,189 +/- 586 pg/ml) where as sEng was undetectable. Circulating sFlt-1 increased from 245 +/- 38 to 3,920 +/- 798 pg/ml in response to AT1-AA induced hypertension. sFlt-1 levels were higher (3,400 +/- 350 vs. 2,480 +/- 900 pg/ml) in placental explants from AT1-AA infused rats (n = 12) than NP rats (n = 7). In addition, sEndoglin increased from 30 +/- 2.7 to 44 +/- 3.3 pg/ml (P < 0.047) in AT1-AA infused rats but was undetectable in the media of the placental explants. CONCLUSIONS These data suggest that immune factors may serve as an important stimulus for both sFlt-1 and sEndoglin production in response to placental ischemia.

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.

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.

Effects of 17-Hydroxyprogesterone on Tumor Necrosis Factor-α-Induced Hypertension During Pregnancy

BACKGROUND Inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha) may be an important link between placental ischemia and hypertension in preeclampsia. We examined the effect of 17-hydroxyprogesterone caproate (17-OHP) on TNF-alpha-stimulated endothelin (ET) production and hypertension during pregnancy. METHODS TNF-alpha-stimulated ET was examined from endothelial cells cultured in the presence and absence of progesterone. Blood pressure and tissue ET-1 were measured in the following groups of pregnant rats: controls, 17-OHP (3.32 mg/kg), TNF-alpha treated (50 ng/day), TNF-alpha treated+17-OHP. RESULTS Progesterone abolished TNF-alpha-stimulated ET-1 from endothelial cells. TNF-alpha-induced hypertension was associated with significant increases in renal and placental ET-1. Administration of 17-OHP attenuated TNF-alpha-induced hypertension and decreased renal ET-1. CONCLUSION Progesterone directly abolished TNF-alpha-stimulated ET-1 and attenuated TNF-alpha-induced hypertension, possibly via suppression of the renal ET-1 system. These data suggest that treatment with progesterone of hypertension associated with elevated cytokines during pregnancy may be worthy of further consideration.

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.

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.

Effect of antenatal tocolysis on neonatal outcomes

Objective: Detail adverse neonatal effects in pregnancies treated with indomethacin (I), magnesium sulfate (M) or nifedipine (N). Methods: Women in acute preterm labor with cervical dilatation 1–6 cm were randomized to receive one of three first-line tocolytic drugs. Results: There were 317 neonates (I = 103, M = 95, N = 119) whose mothers were treated with tocolytic therapy. There was no difference in gestational age at randomization (average 28.6 weeks’ gestation) or at delivery (31.6 weeks’ gestation, p = 0.551), birth weight (p = 0.871) or ventilator days (p = 0.089) between the three groups. Neonatal morbidity was not different between the three groups; respiratory distress syndrome (p = 0.086), patent ductus arteriosus (p = 0.592), sepsis (p = 0.590), necrotizing enterocolitis (p = 0.770), intraventricular hemorrhage (p = 0.669) and periventricular leukomalacia (p = 0.124). Conclusions: There were no statistically significant differences between the three tocolytics as far as composite neonatal morbidity or mortality was concerned.

17-hydroxyprogesterone blunts the hypertensive response associated with reductions in uterine perfusion pressure in pregnant rats

OBJECTIVE Reduction in uteroplacental perfusion (RUPP) in pregnant rats is associated with hypertension, elevated cytokines, and activation of the endothelin (ET-1) system. Our objective was to determine whether the antiinflammatory properties of 17-alpha-hydroxyprogesterone caproate (17 OHP) reduce cytokine-stimulated vasoactive pathways that are associated with hypertension in response to placental ischemia. STUDY DESIGN Mean arterial pressure (MAP), tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-6, and renal ET-1 were measured in the following: pregnant controls, pregnant controls plus 17 OHP (6.6 mg/kg), RUPP rats, and RUPP rats plus 17 OHP. RESULTS MAP increased 29 mm Hg in RUPP rats compared with pregnant controls (P < .001), whereas in RUPP plus 17 OHP rats, MAP increased only 19 mm Hg (P < .05). TNF-alpha and IL-6 increased 2- to 3-fold, respectively, in response to placental ischemia but was normalized in RUPP rats treated with 17 OHP. ET-1 increased 3-fold in RUPP rats but was markedly less in RUPP plus 17 OHP rats. CONCLUSION 17 OHP blunts hypertension associated with RUPP, possibly via suppression of cytokine-stimulated ET-1 activation.

A multicenter assessment of 1,177 cases of shoulder dystocia: lessons learned.

The purposes of this review were to describe deliveries complicated by shoulder dystocia (SD) at three tertiary centers and discern the differences between SD with and without brachial plexus injury (BPI). The inclusion criteria for this multicenter, retrospective study were singletons, delivered vaginally with SD. To discern the risk factors for SD with and without injury, a case (SD and BPI) versus control (3 SD without injury at the same institution) design was used. Multiple linear regression was employed. Over a 7-year period, among 46,637 vaginal deliveries, SD occurred in 1,177 cases (2.5%) and BPI was noted in 11%. The results of multiple regression indicate that gestational age, operative delivery, and the number of maneuvers and concomitant fracture (4%) were statistically associated with BPI following SD (p < 0.001). SD was not associated with BPI in 89% and 88% of the cases that were resolved with McRoberts maneuver and suprapubic pressure, whereas only 0.2% of cases were litigated.