Marie Darby

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.

CD4+ T Cells Play a Critical Role in Mediating Hypertension in Response to Placental Ischemia

Similar to preeclamptic women, hypertension in the chronic Reduced Uterine Perfusion Pressure Rat Model Of Preeclampsia (RUPP) is associated with increased CD4+ T cells, cytokines, sFlt-1 and agonistic autoantibodies to the AngII receptor (AT1-AA). We examined the effect inhibition of T cell co-stimulation in RUPP rats treated with (A) (abatacept, 250 mg/kg, infused i.v. at gestation day 13), on hypertension and sFlt-1, TNF-α and AT1-AA. RUPP surgical procedure was performed on day 14. On day 19 MAP increased from 94+2 mmHg in Normal Pregnant (NP) to 123 ± 3 mmHg in RUPP control rats. This response was attenuated by Abatacept, MAP was 104 ± 2 mmHg in RUPP ± A, and 96 ± 2 mmHg NP ± A. Percent circulating CD4+ T cells were 66 ± 3% in RUPPs compared to 55 ± 3% NP rats (p<0.04) but were normalized in RUPP ± A rats (54 ± 3%). The twofold increase in TNF alpha seen in RUPPs (277 ± 47 pg/ml) was decreased to 80 ± 18 pg/ml in RUPP+A. Placental sFlt-1 was reduced 70 % to 151 ± 28 in RUPP ± A compared 488 ± 61 pg/ml in RUPP (p<0.001). AT1-AA decreased from 20 ± 0.8 bpm in control RUPP to 6 ± 0.7 bpm in RUPP ± A. We next determined the effect of RUPP in causing hypertension in pregnant T cell deficient rats by examining MAP in NP (123 ± 5 mmHg) and RUPP athymic nude rats (123 ± 7 mmHg). In the absence of T cells, hypertension in response to placental ischemia was completely abolished. Collectively these data indicate that CD4+ Tcells in response to placental ischemia play an important role in the pathophysiology of hypertension associated with preeclampsia.

Vitamin D supplementation improves pathophysiology in a rat model of preeclampsia

Deficiency of vitamin D (VD) is associated with preeclampsia (PE), a hypertensive disorder of pregnancy characterized by proinflammatory immune activation. We sought to determine whether VD supplementation would reduce the pathophysiology and hypertension associated with the reduced uterine perfusion pressure (RUPP) rat model of PE. Normal pregnant (NP) and RUPP rats were supplemented with VD2 or VD3 (270 IU and 15 IU/day, respectively) on gestation days 14-18 and mean arterial pressures (MAPs) measured on day 19. MAP increased in RUPP to 123 ± 2 mmHg compared with 102 ± 3 mmHg in NP and decreased to 113 ± 3 mmHg with VD2 and 115 ± 3 mmHg with VD3 in RUPP rats. Circulating CD4+ T cells increased in RUPP to 7.90 ± 1.36% lymphocytes compared with 2.04 ± 0.67% in NP but was lowered to 0.90 ± 0.19% with VD2 and 4.26 ± 1.55% with VD3 in RUPP rats. AT1-AA, measured by chronotropic assay, decreased from 19.5 ± 0.4 bpm in RUPPs to 8.3 ± 0.5 bpm with VD2 and to 15.4 ± 0.7 bpm with VD3. Renal cortex endothelin-1 (ET-1) expression was increased in RUPP rats (11.6 ± 2.1-fold change from NP) and decreased with both VD2 (3.3 ± 1.1-fold) and VD3 (3.1 ± 0.6-fold) supplementation in RUPP rats. Plasma-soluble FMS-like tyrosine kinase-1 (sFlt-1) was also reduced to 74.2 ± 6.6 pg/ml in VD2-treated and 91.0 ± 16.1 pg/ml in VD3-treated RUPP rats compared with 132.7 ± 19.9 pg/ml in RUPP rats. VD treatment reduced CD4+ T cells, AT1-AA, ET-1, sFlt-1, and blood pressure in the RUPP rat model of PE and could be an avenue to improve treatment of hypertension in response to placental ischemia.

Maternal hemodynamics by thoracic impedance cardiography for normal pregnancy and the postpartum period.

OBJECTIVE: To establish normative impedance cardiography values for the second half of pregnancy and up to 48 hours postpartum after either vaginal or cesarean delivery. METHODS: A single-center prospective observational institutional review board-approved study of normotensive women (n=168) using thoracic impedance cardiography performed at specific times during gestation. Antepartum testing was performed at three time periods: 20–27 weeks, 28–33 weeks, and 34–40 weeks of gestation. Postpartum testing was undertaken after the immediate puerperium at 6–23 hours and 24–48 hours after vaginal or cesarean delivery. Data analysis was performed using STATA software; data are expressed as mean±standard deviation. RESULTS: All seven of the patient groups studied were comparable with regard to demographic features; 80% of the study participants were African American. Group means obtained between 20 and 40 weeks of gestation and postpartum after vaginal and cesarean delivery fell within the “normal range” of the hemodynamic graph that was developed to associate mean arterial pressure and systemic vascular resistance. The thoracic fluid content group means in both vaginal and cesarean delivery groups were higher than the antepartum patient groups. The thoracic fluid content mean after cesarean delivery at 48 hours is significantly higher than the mean value recorded between 20 and 27 weeks of gestation (P<.05). The systemic vascular resistance systemic vascular resistance means in each of the postpartum groups were significantly higher than the late second-trimester group means recorded at 20–27 weeks of gestation (P<.05). CONCLUSION: The normative values reported in this investigation can be used to interpret and assess similarly tested patients with hypertensive or otherwise complicated pregnancy. LEVEL OF EVIDENCE: III

Hypertension, inflammation and T lymphocytes are increased in a rat model of HELLP syndrome

Objective: An animal model of hemolysis, elevated liver enzymes, low platelet count (HELLP) was used to determine if T lymphocytes accompany hypertension and increased inflammatory cytokines. Methods: sFlt-1 (4.7 µg/kg/day) and sEndoglin (7 µg/kg/day) were infused into normal pregnant rats (HELLP rats) for 8 days. Results: HELLP was associated with increased mean arterial pressure (p = 0.0001), hemolysis (p = 0.044), elevated liver enzymes (p = 0.027), and reduced platelets (p = 0.035). HELLP rats had increased plasma levels of TNFα (p = 0.039), IL-6 (p = 0.038) and IL-17 (p = 0.04). CD4+ and CD8+ T lymphocytes were increased. Conclusion: These data support the hypothesis that T cells are associated with hypertension and inflammation.

Impedance cardiography assessed treatment of acute severe pregnancy hypertension: a randomized trial

Abstract Objective: Using noninvasive bedside impedance cardiography (ICG), we compared the effectiveness and the hemodynamic impact of intravenous labetalol versus hydralazine for the reduction of acute-onset severe hypertension to ACOG-recommended blood pressure levels (ACOG Committee Opinion 514). Study design: In this prospective randomized pilot study of acutely severe systolic hypertension (≥160 mmHg), pregnant women received either labetalol (L) or hydralazine (H) intravenously and underwent thoracic ICG before and after treatment. Data analysis were performed using STATA software (StataCorp LP, College Station, TX); data are expressed as mean ± SD. Results: About 29 patients completed the study. There was no significant difference in mean arterial pressure (MAP) between groups [H = 119.4 mmHg, L = 117.7 mmHg, mean difference (MD) = 1.73); the estimated MD between baseline and follow-up ICG was −9.17 (p = 0.001, 95% CI: −14.39 to −3.95). There were no significant differences in total peripheral resistance (TPR) between groups (H = 1771.3, L = 1976.97, MD = 205.62) or cardiac output (CO) between groups (H = 5.7, L = 5.1, MD = 0.64) or a significant MD between these at baseline and follow-up. Conclusion: Both drugs performed similarly to achieve ACOG-recommended initial blood pressure reduction safely without side effects or excessive acute hemodynamic profile correction toward normal pregnancy values.

Using case reports to determine when liver bleeding occurs during disease progression in HELLP syndrome

Hepatic hemorrhage occurs in less than 5% of patients with hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome but it is a profound cause of maternal/perinatal morbidity and mortality.

A complicated role for the renin-angiotensin system during pregnancy: highlighting the importance of drug discovery.

Introduction: Blood pressure management is recommended to avoid maternal cerebrovascular or cardiovascular compromise during pregnancy. Current antihypertensive treatment during pregnancy with positive safety profiles includes labetalol, hydralazine, methyldopa and nifedipine. Areas covered: Many earlier animal and human studies indicate that angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) are associated with fetopathy; therefore, these drugs are contraindicated during pregnancy, especially if these medications were taken during the second and third trimesters. The role of the RAS is quite complex, with fetal development heavily dependent on its appropriate expression and function. New findings indicate that the placental unit expresses its own RAS in order to regulate angiogenesis. Multiple studies have shown that women with abnormal uterine doppler sonography produce an agonistic autoantibody to the angiotensin I receptor, implicating a role for RAS function and regulation in abnormal pregnancies. Importantly, interruption of a normal RAS compromises fetal development. Expert opinion: Traditional medications that inhibit components of RAS for long-term hypertension control are not appropriate for use before or during pregnancy. Further study and drug discovery are needed to find alternative pathways for treatment of hypertensive disorders when pregnancy is present or a possibility.

Tachysystole Following Cervical Ripening and Induction of Labor Is Not Associated with Adverse Outcomes

Purpose: This study was aimed at determining if significant uterine tachysystole was associated with adverse fetal or neonatal outcomes during cervical ripening and induction of labor. Methods: Women undergoing cervical ripening and subsequent labor induction (n = 905) were assessed for tachysystole, defined as ≥6 contractions in each of 2 consecutive 10-minute windows. Women with ≥3 episodes of tachysystole were compared to women with no tachysystole. Results: Over a 5-year period, 70% of the 905 participants (n = 631) had no tachysystole, 143 had 1 or 2 episodes whereas 131 or 15% had ≥3 episodes (p = 0.991). The cesarean delivery rate was lower among those with tachysystole (28.2 vs. 34.1%), but the difference was not significant (p = 0.197). Non-reassuring fetal tracings were more common in the tachysystole group (14.4 vs. 21.4%, p = 0.017), but the Apgar scores at 5 min and the umbilical cord pH and base excess were similar between the 2 groups (p = 0.502, p = 0.435, and p = 0.535, respectively). Conclusions: Tachysystole was not associated with adverse perinatal outcomes when compared to women with no tachysystole during cervical ripening and induction of labor.