Removal of Soluble Fms-Like Tyrosine Kinase-1 by Dextran Sulfate Apheresis in Preeclampsia.

Preeclampsia is a devastating complication of pregnancy. Soluble Fms-like tyrosine kinase-1 (sFlt-1) is an antiangiogenic protein believed to mediate the signs and symptoms of preeclampsia. We conducted an open pilot study to evaluate the safety and potential efficacy of therapeutic apheresis with a plasma-specific dextran sulfate column to remove circulating sFlt-1 in 11 pregnant women (20-38 years of age) with very preterm preeclampsia (23-32 weeks of gestation, systolic BP ≥140 mmHg or diastolic BP ≥90 mmHg, new onset protein/creatinine ratio >0.30 g/g, and sFlt-1/placental growth factor ratio >85). We evaluated the extent of sFlt-1 removal, proteinuria reduction, pregnancy continuation, and neonatal and fetal safety of apheresis after one (n=6), two (n=4), or three (n=1) apheresis treatments. Mean sFlt-1 levels were reduced by 18% (range 7%-28%) with concomitant reductions of 44% in protein/creatinine ratios. Pregnancy continued for 8 days (range 2-11) and 15 days (range 11-21) in women treated once and multiple times, respectively, compared with 3 days (range 0-14) in untreated contemporaneous preeclampsia controls (n=22). Transient maternal BP reduction during apheresis was managed by withholding pre-apheresis antihypertensive therapy, saline prehydration, and reducing blood flow through the apheresis column. Compared with infants born prematurely to untreated women with and without preeclampsia (n=22 per group), no adverse effects of apheresis were observed. In conclusion, therapeutic apheresis reduced circulating sFlt-1 and proteinuria in women with very preterm preeclampsia and appeared to prolong pregnancy without major adverse maternal or fetal consequences. A controlled trial is warranted to confirm these findings.

Serum levels of the adipokine fibroblast growth factor-21 are increased in preeclampsia.

BACKGROUND: Preeclampsia (PE) is a serious cardiovascular complication in pregnancy, which is associated with an increased future metabolic and cardiovascular risk for mother and newborn. Fibroblast growth factor (FGF)-21 was recently introduced as a novel adipokine improving glucose metabolism in vitro and in vivo. MATERIAL AND METHODS: We investigated serum FGF-21 levels in patients with PE (n=51) as compared to healthy, age-matched controls (n=51) during and 6 months after pregnancy. Furthermore, association of FGF-21 with markers of renal function, glucose and lipid metabolism, as well as inflammation, was elucidated in all individuals. RESULTS: Median maternal FGF-21 serum concentrations adjusted for body mass index and gestational age at blood sampling were significantly, almost 3-fold increased in PE patients (309.6 ng/l) as compared to healthy, age-matched pregnant women (105.2 ng/l) (p<0.001). Furthermore, FGF-21 concentrations were independently and positively correlated with triglycerides whereas an independent and negative association was observed with glomerular filtration rate and low density lipoprotein (LDL) cholesterol in pregnant women. Moreover, FGF-21 serum levels significantly decreased in former PE patients 6 months after pregnancy approaching levels found in control patients. CONCLUSIONS: Maternal FGF-21 serum concentrations are significantly increased in PE during pregnancy. Furthermore, triglycerides, glomerular filtration rate, and LDL cholesterol are independent predictors of circulating FGF-21 in pregnant women.

The course of angiogenic factors in early- vs. late-onset preeclampsia and HELLP syndrome.

AIMS: Preeclampsia (PE) is considered a uniformly progressive disease, however, it shows a different pattern of clinical progression in patients with early (<34 weeks) or late (≥ 34 weeks) onset of the disease. Angiogenic factors such as soluble fms-like tyrosine kinase 1 (sFlt-1) and placental growth factor (PlGF) are closely related to the clinical course of PE. We evaluated sFlt-1 and PlGF levels in the clinical course of PE in women admitted with a diagnosis of PE at different gestational ages. METHODS: This retrospective study included 34 patients with PE, of which 11 patients had HELLP syndrome (over a period of 3 years). Serial measurements of sFlt-1 and PlGF were completed from admission until delivery. Values are presented as mean ± standard deviation. RESULTS: Mean gestational age of admission among women with early onset PE was significantly lower, at 29 ± 3 weeks compared to 37±1 weeks among patients with late onset disease. Mean prolongation of pregnancy was 6 days, which was similar within the two groups. Compared to women with late onset PE, women with early-onset PE had a greater increase in sFlt-1 (11% vs. 3% per day, P<0.05), greater decrease in PlGF levels (21% vs. 10% per day, P=0.30), resulting in a much higher increase in sFlt-1/PlGF ratio (23% vs. 8% per day, P<0.05). Patients with HELLP syndrome showed comparable progression patterns. CONCLUSION: In a similar way to the progressively worsening clinical course observed in women with early onset PE, there were changes in the angiogenic profile that leads to a more anti-angiogenic state in these women with each passing day. These findings may have implications in identification of the women for appropriate patient management and possible future therapies based on the reduction of sFlt-1 levels.

Pilot study of extracorporeal removal of soluble fms-like tyrosine kinase 1 in preeclampsia.

BACKGROUND: Targeted therapies to stabilize the clinical manifestations and prolong pregnancy in preeclampsia do not exist. Soluble fms-like tyrosine kinase 1 (sFlt-1), an alternatively spliced variant of the vascular endothelial growth factor receptor 1, induces a preeclampsia-like phenotype in experimental models and circulates at elevated levels in human preeclampsia. Removing sFlt-1 may benefit women with very preterm (<32 weeks) preeclampsia. METHODS AND RESULTS: We first show that negatively charged dextran sulfate cellulose columns adsorb sFlt-1 in vitro. In 5 women with very preterm preeclampsia and elevated circulating sFlt-1 levels, we next demonstrate that a single dextran sulfate cellulose apheresis treatment reduces circulating sFlt-1 levels in a dose-dependent fashion. Finally, we performed multiple apheresis treatments in 3 additional women with very preterm (gestational age at admission 28, 30, and 27+4 weeks) preeclampsia and elevated circulating sFlt-1 levels. Dextran sulfate apheresis lowered circulating sFlt-1, reduced proteinuria, and stabilized blood pressure without apparent adverse events to mother and fetus. Pregnancy lasted for 15 and 19 days in women treated twice and 23 days in a woman treated 4 times. In each, there was evidence of fetal growth. CONCLUSIONS: This pilot study supports the hypothesis that extracorporeal apheresis can lower circulating sFlt-1 in very preterm preeclampsia. Further studies are warranted to determine whether this intervention safely and effectively prolongs pregnancy and improves maternal and fetal outcomes in this setting.

Maternal and neonatal outcome after vaginal breech delivery of nulliparous versus multiparous women of singletons at term-A prospective evaluation of the Frankfurt breech at term cohort (FRABAT).

INTRODUCTION: The best way to deliver a term breech infant is still a much discussed topic among obstetricians. The question whether nulliparity should be considered an exclusion criterion for an intended vaginal breech delivery is not fully answered. OBJECTIVE: We compared maternal and neonatal outcome of intended vaginal breech deliveries of nulliparous versus multiparous women at term. STUDY DESIGN: We conducted a prospective case-control study between January 2004 and December 2016. 1046 women expecting singletons at term with favorable pelvic measurements were enrolled in the study. RESULTS: Neonatal morbidity and mortality was not significantly different in deliveries of nulliparous (n = 647) versus multiparous (n = 399) women. Nulliparous women had a significantly higher rate of a cesarean section during labor than multiparous women. Maternal birth-injury rates and the use of epidural anesthesia were significantly higher comparing vaginal births of nulliparous (n = 384) versus multiparous (n = 331) women. CONCLUSION: Nulliparity seems not be an exclusion criterion for intended vaginal breech birth at term. It is still important to inform the women of an increased risk of a cesarean section during labor. A clinical management built on this evidence might reduce negative implications for future pregnancies.

Maternal and neonatal outcome after vaginal breech delivery at term of children weighing more or less than 3.8 kg: A FRABAT prospective cohort study.

INTRODUCTION: The clinical management of breech presentations at term is still a controversially discussed issue among clinicians. Clear predictive criteria for planned vaginal breech deliveries are desperately needed to prevent adverse fetal and maternal outcomes and to reduce elective cesarean section rates. The green-top guideline considers an estimated birth weight of 3.8 kg or more an indication to plan a cesarean section despite the lack of respective evidence. OBJECTIVE: To compare maternal and neonatal outcome of vaginal intended breech deliveries of births with children with a birth weight of 2.5 kg- 3.79 kg and children with a birth weight of 3.8 kg and more. DESIGN: Prospective cohort study. SAMPLE: All vaginal intended deliveries out of a breech position of newborns weighing between 2.5 kg and 4.5 kg at the Obstetrics department at Goethe University Hospital Frankfurt from January 2004 until December 2016. METHODS: Neonatal and maternal outcome of a light weight group (LWG) (< 3.8 kg) was compared to and a high weight group (HWG) (≥ 3.8 kg) using Pearson's Chi Square test and Fishers exact test. A logistic regression analysis was performed to detect an association between cesarean section rates, fetal outcome and the birth weight. RESULTS: No difference in neonatal morbidity was detected between the HWG (1.8%, n = 166) and the LWG (2.6%, n = 888). Cesarean section rate was significantly higher in the HWG with 45.2% in comparison to 28.8% in the LWG with an odds ratio of 1.57 (95% CI 1.29-1.91, p<0.0001). In vaginal deliveries, a high birth weight was not associated with an increased risk of maternal birth injuries (LWG in vaginal deliveries: 74.3%, HWG in vaginal deliveries: 73.6%; p = 0.887; OR = 1.9 (95% CI 0.9-1.1)). CONCLUSION: A fetal weight above 3.79 kg does not predict increased maternal or infant morbidity after delivery from breech presentation at term. Neither the literature nor our analyses document evidence for threshold of estimated birth weight that is associated with maternal and/or infant morbidity. However, patients should be informed about an increased likelihood of cesarean sections during labor when attempting vaginal birth from breech position at term in order to reach an informed shared decision concerning the birth strategy. Further investigations in multi center settings are needed to advance international guidelines on vaginal breech deliveries in the context of estimated birth weight and its impact on perinatal outcome.

Serum levels of growth arrest specific protein 6 are increased in preeclampsia.

Preeclampsia (PE) contributes to maternal and fetal morbidity and mortality worldwide. Moreover, it is associated with an increased future metabolic and cardiovascular risk for mother and newborn. Recently, growth arrest specific protein (Gas) 6 has been introduced as a novel metabolic risk factor with anti-angiogenic, pro-atherogenic, and pro-adipogenic properties. In the current study, we investigated serum concentrations of Gas6 in patients with PE (n=51) as compared to healthy, age-matched controls (n=51) during and 6 months after pregnancy. Furthermore, association of Gas6 with markers of renal function, glucose and lipid metabolism, as well as inflammation, was assessed in all individuals. Median maternal Gas6 serum levels adjusted for body mass index and gestational age at blood sampling were significantly increased in PE patients (5.7 µg/l) as compared to healthy, age-matched pregnant women (4.6 µg/l) (p<0.05). Furthermore, Gas6 concentrations positively correlated with blood pressure, creatinine, free fatty acids, C-reactive protein, leptin, and adiponectin during pregnancy. Moreover, leptin and adiponectin remained independently associated with Gas6 levels in multivariate analysis. Gas6 serum levels 6 months after pregnancy were not significantly different between former PE and control patients. Taken together, maternal Gas6 serum concentrations are significantly increased in PE during pregnancy. Furthermore, the adipokines leptin and adiponectin are independent predictors of circulating Gas6 in pregnant women.

Serum levels of the adipokine chemerin are increased in preeclampsia during and 6 months after pregnancy.

UNLABELLED: Preeclampsia is a serious cardiovascular complication in pregnancy which is associated with an increased future metabolic and cardiovascular risk for mother and newborn. Recently, chemerin was introduced as a novel adipokine inducing insulin resistance in vitro and in vivo. In the current study, we investigated serum concentrations of chemerin by ELISA in control and preeclampsia patients during pregnancy ( CONTROL: n=37, preeclampsia: n=37) and 6 months after delivery ( CONTROL: n=35, preeclampsia: n=36). Furthermore, the association between chemerin and markers of renal function, glucose and lipid metabolism, as well as inflammation was studied in pregnant patients. Median maternal chemerin concentrations were significantly elevated in preeclampsia patients (249.5 [range: 123.1-366.9] µg/l) as compared to controls (204.8 [138.5-280.8] µg/l) (p<0.001). Furthermore, chemerin serum levels positively correlated with blood pressure, creatinine, free fatty acids, cholesterol, triglycerides (TG), leptin, adiponectin, and C-reactive protein in univariate analyses. In multivariate analyses, TG and leptin remained independently associated with circulating chemerin. Interestingly, median chemerin concentrations 6 months after delivery remained significantly higher in former preeclampsia patients (196.0 [119.8-368.7] µg/l) as compared to controls (152.2 [102.8-216.4] µg/l). Taken together, maternal chemerin serum concentrations are significantly increased in preeclampsia during and after pregnancy. Furthermore, TG and leptin are independent predictors of circulating chemerin during pregnancy.