Rilzabrutinib, an Oral BTK Inhibitor, in Immune Thrombocytopenia.

BACKGROUND: Rilzabrutinib, an oral, reversible covalent inhibitor of Bruton's tyrosine kinase, may increase platelet counts in patients with immune thrombocytopenia by means of dual mechanisms of action: decreased macrophage (Fcγ receptor)-mediated platelet destruction and reduced production of pathogenic autoantibodies. METHODS: In an international, adaptive, open-label, dose-finding, phase 1-2 clinical trial, we evaluated rilzabrutinib therapy in previously treated patients with immune thrombocytopenia. We used intrapatient dose escalation of oral rilzabrutinib over a period of 24 weeks; the lowest starting dose was 200 mg once daily, with higher starting doses of 400 mg once daily, 300 mg twice daily, and 400 mg twice daily. The primary end points were safety and platelet response (defined as at least two consecutive platelet counts of ≥50×103 per cubic millimeter and an increase from baseline of ≥20×103 per cubic millimeter without the use of rescue medication). RESULTS: Sixty patients were enrolled. At baseline, the median platelet count was 15×103 per cubic millimeter, the median duration of disease was 6.3 years, and patients had received a median of four different immune thrombocytopenia therapies previously. All the treatment-related adverse events were of grade 1 or 2 and transient. There were no treatment-related bleeding or thrombotic events of grade 2 or higher. At a median of 167.5 days (range, 4 to 293) of treatment, 24 of 60 patients (40%) overall and 18 of the 45 patients (40%) who had started rilzabrutinib treatment at the highest dose met the primary end point of platelet response. The median time to the first platelet count of at least 50×103 per cubic millimeter was 11.5 days. Among patients with a primary platelet response, the mean percentage of weeks with a platelet count of at least 50×103 per cubic millimeter was 65%. CONCLUSIONS: Rilzabrutinib was active and associated with only low-level toxic effects at all dose levels. The dose of 400 mg twice daily was identified as the dose for further testing. Overall, rilzabrutinib showed a rapid and durable clinical activity that improved with length of treatment. (Funded by Sanofi; ClinicalTrials.gov number, NCT03395210; EudraCT number, 2017-004012-19.).

Ph- myeloproliferative neoplasms and the related risk factors for stroke occurrence: Results from a registry of patients treated with Anagrelide.

Arterial thrombosis is a common complication in patients with Ph- myeloproliferative neoplasms (MPN). We searched for the risk factors of stroke in MPN patients from anagrelide registry. We analyzed the potential risk factors triggering a stroke/TIA event in 249 MPN patients with previous stroke (n = 168) or Transient Ischemic Attack (TIA) (n = 140), and in 1,193 MPN control subjects (without clinical history of thrombosis). These patients were registered in a prospective manner, providing a follow-up period after Anagrelide treatment. The median age of the patients in the experimental group was of 56 years of age (ranging from 34-76) and of 53 years of age (ranging from 26-74) in the control group (p < 0.001). Using a multivariate model, we determined the following as risk factors: JAK2V617F mutation (OR 2.106, 1.458-3.043, p = 0.006), age (OR 1.017/year, 1.005-1,029, p = 0.006), male gender (OR 1.419, 1.057-1.903, p = 0.020), MPN diagnosis (OR for PMF 0.649, 0.446-0.944, p = 0.024), BMI (OR 0.687 for BMI > 25, 0.473-0.999, p = 0.05) and high TAG levels (OR 1.734, 1.162-2.586, p = 0.008), all of which were statistically significant for CMP development. Concerning the risk factors for thrombophilia, only the antiphospholipid syndrome (OR 1.994, 1.017-3.91, p = 0.048) was noteworthy in a stroke-relevant context. There was no significant difference between the blood count of the patients prior to a stroke event and the control group, both of which were under a cytoreductive treatment. We found that age, male gender, JAK2V617F mutation, previous venous thrombosis, and hypertriglyceridemia represent independent risk factors for the occurrence of a stroke in Ph- MPN patients.

Sacrospinous hysteropexy - an alternative in primary surgical treatment of apical compartment prolapse

OBJECTIVE: To present a surgical treatment of pelvic organ prolapse and its outcomes according to the literature. METHODS: PubMed database search. CONCLUSION: Pelvic organ prolapse is a common diagnosis with prevalence around 40% of female population. Vaginal delivery, especially with levator ani trauma, increasing age and obesity are the basic risk factors. Native tissue repair is a possible surgical treatment. Unfortunately, concomitant hysterectomy is still a very common procedure. It is established that uterus plays a passive role in pelvic organ prolapse. Sparing of the uterus keeps the original fixation structures and compartments intact and provides a solid tissue to anchor the stitches. Patients with benign and malign uterine diseases cannot have their uterus spared. In sacrospinous hysteropexy, nonabsorbable sutures are passed through the namesaked ligament on one or both sides to elevate the uterus. Several studies and their metaanalyses show comparable anatomical and functional outcomes with shorter operation time, decreased blood loss, faster recovery and lower complication rates in comparison with hysterectomy and uterosacral ligament fixation. In a prospective randomized control trial, sacrospinous hysteropexy provides significantly lower reoperation rate for apical compartment prolapse in a long-term follow-up. It is a safe and effective procedure for patients who wish to keep their uterus in place. Sacrospinous hysteropexy is an alternative in primary surgical treatment of pelvic organ prolapse.

Prelabor rupture of membranes between 34 and 37 weeks: the intraamniotic inflammatory response and neonatal outcomes.

OBJECTIVE: We sought to determine the influence of microbial invasion of the amniotic cavity (MIAC) and acute histologic chorioamnionitis (HCA) on the intensity of the intraamniotic inflammatory response and neonatal morbidity in preterm prelabor rupture of membranes (PPROM) between 34-37 weeks. STUDY DESIGN: This study included 99 women with singleton pregnancies complicated by PPROM between the gestational ages of 34-37 weeks. Amniocenteses were performed at the time of admission, and MIAC and amniotic fluid interleukin-6 concentrations were determined. After delivery, the placenta was evaluated for the presence of HCA. RESULTS: Women with both MIAC and HCA had the highest intraamniotic inflammatory response, which was mediated by interleukin-6 concentrations (both MIAC and HCA: median 2164.0 pg/mL; HCA alone: median 654.8 pg/mL; MIAC alone: median 784.1 pg/mL; neither MIAC nor HCA: median 383.0 pg/mL; P < .0001) and the highest incidence of newborns with early-onset sepsis (P = .02). CONCLUSION: Both MIAC and HCA affect the intensity of the intraamniotic inflammatory response and the incidence of early-onset sepsis following PPROM between 34-37 weeks. The intensity of the intraamniotic inflammatory response should be considered in the clinical management of PPROM between 34-37 weeks.

Bedside assessment of amniotic fluid interleukin-6 in preterm prelabor rupture of membranes.

OBJECTIVE: The objective of the study was to determine the diagnostic indices and predictive values by bedside assessment of amniotic fluid interleukin-6 (IL-6) concentration in the identification of microbial invasion of the amniotic cavity (MIAC) and/or histological chorioamnionitis (HCA) in patients with preterm prelabor rupture of membranes. STUDY DESIGN: One hundred twenty-four women with singleton pregnancies were included in this study. The amniotic fluid was sampled by transabdominal amniocentesis at the time of admission. IL-6 concentrations were assessed with an immunoassay. RESULTS: The presence of MIAC, HCA, or the coexistence of both was associated with higher amniotic fluid concentrations of IL-6 in both a crude and adjusted analysis. The amniotic fluid concentration of IL-6 of 1000 pg/mL was determined to be the best cutoff value for the prediction of MIAC (sensitivity of 50%, specificity of 95%, positive predictive value of 82%, negative predictive value of 81%, and likelihood ratio of 8.4) or both MIAC and HCA (sensitivity of 60%, specificity of 94%, positive predictive value of 75%, negative predictive value of 88%, and likelihood ratio of 9.4). CONCLUSION: The bedside assessment of amniotic fluid IL-6 seems to be an easy, rapid, and inexpensive method for the prediction of MIAC or both MIAC and HCA in pregnancies complicated by preterm prelabor rupture of membranes.

Lymphocyte subpopulations: a potential predictor of a response in patients with immune thrombocytopenia.

OBJECTIVES: Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder caused by increased platelet destruction and altered production. Despite the well-described pathophysiological background of immune dysregulation, current treatment guidelines consist of monotherapy with different drugs, with no tool to predict which patient is more suitable for each therapeutic modality. METHODS: In our study, we attempted to determine differences in the immune setting, comparing the patients' responses to administered therapy. During 12-month follow-up, we assessed blood count, antiplatelet autoantibodies, and T lymphocyte subsets in peripheral blood in 35 patients with ITP (newly diagnosed or relapsed disease). RESULTS: Our data show that the value of antiplatelet autoantibodies, the percentage of cytotoxic T lymphocytes, and the immunoregulatory index (IRI, CD4+ / CD8+ T cell ratio) differ significantly by treatment response. Responders have a higher IRI (median 2.1 vs. 1.5 in non-responders, P = 0.04), higher antiplatelet autoantibodies (median 58 vs. 20% in non-responders, P = 0.01) and lower relative CD8+ T cells count (P = 0.02) before treatment. DISCUSSION: The results suggest that immunological parameters (antiplatelet autoantibodies, relative CD8+ T cell count and IRI) could be used as prognostic tools for a worse clinical outcome in patients with ITP. CONCLUSION: These biomarkers could be utilized for stratification and eventually selection of treatment preferring combination therapy.

Long-term treatment with rilzabrutinib in patients with immune thrombocytopenia.

ABSTRACT: Immune thrombocytopenia (ITP) is an autoimmune disease associated with autoantibody-mediated platelet destruction and impaired platelet production, resulting in thrombocytopenia and a predisposition to bleeding. The ongoing, global phase 1/2 study showed that rilzabrutinib, a Bruton tyrosine kinase inhibitor specifically developed to treat autoimmune disorders, could be an efficacious and well-tolerated treatment for ITP. Clinical activity, durability of response, and safety were evaluated in 16 responding patients who continued rilzabrutinib 400 mg twice daily in the long-term extension (LTE) study. At LTE entry, the median platelet count was 87 × 109/L in all patients, 68 × 109/L in those who had rilzabrutinib monotherapy (n = 5), and 156 × 109/L in patients who received concomitant ITP medication (thrombopoietin-receptor agonists and/or corticosteroids, n = 11). At a median duration of treatment of 478 days (range, 303-764), 11 of 16 patients (69%) continued to receive rilzabrutinib. A platelet count of ≥50 × 109/L was reported in 93% of patients for more than half of their monthly visits. The median percentage of LTE weeks with platelet counts ≥30 × 109/L and ≥50 × 109/L was 100% and 88%, respectively. Five patients discontinued concomitant ITP therapy and maintained median platelet counts of 106 × 109/L at 3 to 6 months after stopping concomitant ITP therapy. Adverse events related to treatment were grade 1 or 2 and transient, with no bleeding, thrombotic, or serious adverse events. With continued rilzabrutinib treatment in the LTE, platelet responses were durable and stable over time with no new safety signals. This trial is registered at www.clinicaltrials.gov as #NCT03395210 and www.clinicaltrialsregister.eu as EudraCT 2017-004012-19.

Ultrasound measurement of the transverse diameter of the fetal thymus in pregnancies complicated by the preterm prelabor rupture of membranes.

PURPOSE: To determine whether the measurement of the transverse diameter of the fetal thymus is of value in the identification of either histologic chorioamnionitis or funisitis in pregnancies complicated by preterm prelabor rupture of membranes (PPROM). METHODS: The transverse diameter of the fetal thymus was measured in 216 fetuses from PPROM pregnancies. A small thymus was defined as a transverse thymic diameter below the fifth percentile according to a previously published nomogram. The placenta, the fetal membranes, and the umbilical cord were assessed for the presence of inflammation. RESULTS: A small thymus was identified in 69% (150/216) of fetuses. A small thymus was present in 80% (106/133) and 88% (36/41) of women with histologic chorioamnionitis or funisitis, respectively. The presence of a small thymus had a sensitivity of 79%, specificity of 47%, positive predictive value of 71%, negative predictive value of 59% for the identification of chorioamnionitis (p < 0.0001; odds ratio 3.5) and a sensitivity of 88%, specificity of 35%, positive predictive value of 24%, and negative predictive value of 92% in the identification of funisitis (p = 0.004; odds ratio 4.4). CONCLUSIONS: The sonographic finding of a small thymus is a sensitive indicator of histologic chorioamnionitis or funisitis; low specificity excludes it as a possible clinical implication in the management of PPROM pregnancies.

Pulsation of the fetal splenic vein--a potential ultrasound marker of histological chorioamnionitis and funisitis in women with preterm prelabor rupture of membranes.

The fetal spleen is involved in the response to intrauterine infection and inflammation. The flow pattern of its vein is not pulsatile in normal conditions. The aim of the study was to determine whether the presence of histological chorioamnionitis and funisitis is associated with a continuous or pulsatile flow pattern in the fetal splenic vein. We performed a prospective study including 79 women with preterm prelabor rupture of membranes. We found a relation between pulsation in the splenic vein and histological chorioamnionitis (likelihood ratio 13.2), as well as funisitis (likelihood ratio 5.7). Ultrasound evaluation of the splenic vein could be a non-invasive tool for the prediction of these inflammatory complications.

Beneficial effect of plasma exchange in the treatment of toxic epidermal necrolysis: a series of four cases.

INTRODUCTION: Toxic epidermal necrolysis (TEN) is a rare, life-threatening disease with a high mortality rate that is linked to drug toxicity. There is a lack of data about the underlying pathophysiologic mechanisms and treatment options. The only widely accepted treatment of TEN is withdrawal of the offending drug followed by supportive care. The potential roles of corticosteroids, intravenous immunoglobulin (IVIG) and plasmapheresis (TPE) remain controversial. AIMS: We present four patients with severe TEN (all with >80% involvement of body surface) who were treated with TPE following unsuccessful treatment with corticosteroids/IVIG. METHODS: TPE was performed using a COBE Spectra blood cell separator. ACD-A was used as anticoagulant fluid and the target-washed plasma volume was one body volume. Plasma was replaced by a 5% solution of human albumin + Ringer's lactate. RESULTS: The mean number of TPE sessions was 5.25 ± 2.22 (range 3-8). Drugs were implicated as an etiologic agent in each case. TPE led to prompt improvement of acute condition and general health as well as halting of disease progression. Additionally, the restoration of the epithelium began in all four patients. CONCLUSION: Plasmapheresis should be considered as an alternative treatment modality for patients with the most severe form of TEN if initial treatment with other agents, including corticosteroids and/or IVIG, fails. Drugs were suspected to be the cause of TEN in all four cases.

Mitochondrial Respiration of Platelets: Comparison of Isolation Methods.

Multiple non-aggregatory functions of human platelets (PLT) are widely acknowledged, yet their functional examination is limited mainly due to a lack of standardized isolation and analytic methods. Platelet apheresis (PA) is an established clinical method for PLT isolation aiming at the treatment of bleeding diathesis in severe thrombocytopenia. On the other hand, density gradient centrifugation (DC) is an isolation method applied in research for the analysis of the mitochondrial metabolic profile of oxidative phosphorylation (OXPHOS) in PLT obtained from small samples of human blood. We studied PLT obtained from 29 healthy donors by high-resolution respirometry for comparison of PA and DC isolates. ROUTINE respiration and electron transfer capacity of living PLT isolated by PA were significantly higher than in the DC group, whereas plasma membrane permeabilization resulted in a 57% decrease of succinate oxidation in PA compared to DC. These differences were eliminated after washing the PA platelets with phosphate buffer containing 10 mmol·L-1 ethylene glycol-bis (2-aminoethyl ether)-N,N,N',N'-tetra-acetic acid, suggesting that several components, particularly Ca2+ and fuel substrates, were carried over into the respiratory assay from the serum in PA. A simple washing step was sufficient to enable functional mitochondrial analysis in subsamples obtained from PA. The combination of the standard clinical PA isolation procedure with PLT quality control and routine mitochondrial OXPHOS diagnostics meets an acute clinical demand in biomedical research of patients suffering from thrombocytopenia and metabolic diseases.

Impact of Antibiotics Associated with the Development of Toxic Epidermal Necrolysis on Early and Late-Onset Infectious Complications.

Toxic epidermal necrolysis (TEN) is a rare disease, which predominantly manifests as damage to the skin and mucosa. Antibiotics count among the most common triggers of this hypersensitive reaction. Patients with TEN are highly susceptible to infectious complications due to the loss of protective barriers and immunosuppressant therapy. The aim of this study was to investigate the potential relationship between antibiotics used before the development of TEN and early and late-onset infectious complications in TEN patients. In this European multicentric retrospective study (Central European Lyell syndrome: therapeutic evaluation (CELESTE)), records showed that 18 patients with TEN used antibiotics (mostly aminopenicillins) before the disease development (group 1), while in 21 patients, TEN was triggered by another factor (group 2). The incidence of late-onset infectious complications (5 or more days after the transfer to the hospital) caused by Gram-positive bacteria (especially by Enterococcus faecalis/faecium) was significantly higher in group 1 than in group 2 (82.4% vs. 35.0%, p = 0.007/p corr = 0.014) while no statistically significant difference was observed between groups of patients with infection caused by Gram-negative bacteria, yeasts, and filamentous fungi (p > 0.05). Patients with post-antibiotic development of TEN are critically predisposed to late-onset infectious complications caused by Gram-positive bacteria, which may result from the dissemination of these bacteria from the primary focus.

Cerebral venous thrombosis after a cesarean delivery.

Cerebral venous thrombosis (CVT) is a serious condition affecting mostly women. This report concerns two cases of women who developed CVT within 14 days of cesarean delivery. Magnetic resonance angiography of the brain (venous phase) is the best modality to diagnose the condition, and parenteral application of low-molecular-weight heparin is the most beneficial treatment. The first patient was found to have an elevated factor VIII level. In the second patient, homozygosity of the C677T mutation in the 5,10-methylenetetrahydrofolate reductase gene was found. The puerperal period and Cesarean Section (CS) are risk factors for thrombotic complications, including CVT. It is necessary to search for risk factors in a patient's history and within the group of at-risk patients to prolong preventive administration of low molecular weight heparin (LMWH). CVT (including puerperium related) is not a detrimental to future pregnancies.

Heparin-induced thrombocytopenia treated with fondaparinux: single center experience.

BACKGROUND: Heparin-induced thrombocytopenia (HIT) is the most frequent drug-induced, immune-mediated thrombocytopenia. It is associated with significant morbidity and mortality. Anticoagulation with heparin must be stopped immediately and replaced by some suggested alternative - lepirudin, danaparoid or argatroban. Fondaparinux has been also successfully used in HIT. METHODS: We present a cohort of 10 patients diagnosed with HIT and treated in a university hospital in a period of four years. Diagnosis was based on Keeling´s scoring system, screening immunologic test for HIT (STic EXPERT® HIT) and sandwich ELISA (detection of IgG/heparin-PF4 antibodies). While other alternative anticoagulants are not readily available in our hospital, we used fondaparinux in all cases. RESULTS: From 2014 to 2018, eight males and two females (mean age 67 years, range 46-86 years) were diagnosed with HIT in our hospital. This complication developed in 9 cases after low-molecular-weight heparin and in one after heparin flushes in hemodialysis. A drop-in platelet count developed in all patients, thrombotic complications in 7 and skin necrosis in 2 cases. Fondaparinux was used in all patients, including two cases with severe renal impairment, the dose was chosen individually. We observed complete platelet recovery in all cases. One patient died because of advanced malignancy, others did not have any complication. In 6 cases we switched to oral anticoagulation after platelet recovery. CONCLUSIONS: In our group of 10 HIT patients fondaparinux was shown to be both safe and effective, even in those with severe renal impairment. Additional studies are warranted to confirm this observation.

Selected metabolic parameters and the risk for uterine fibroids.

OBJECTIVE: To analyze the possible association between insulin resistance and dyslipidemia with uterine fibroids, using objective metabolic measurements. METHOD: A cross-sectional study of 56 women with uterine fibroids (case group) and 20 women without fibroids (control group). Levels of fasting glucose, insulin, C-peptide, sex hormone-binding globulin, and the lipid panel were measured. The short insulin tolerance test was performed. Body mass index, atherogenic index, and the indicator of insulin resistance (Kitt) were also calculated. RESULTS: Women with fibroids had significantly higher levels of serum HDL-cholesterol compared with control patients (1.8+/-0.3 vs 1.6+/-0.5; P<0.05). Women with fibroids aged 30-45 years had significantly lower LDL-cholesterol levels than comparative control patients (2.9+/-0.7 vs 3.4+/-0.9; P<0.05). A positive correlation between volume of the largest fibroid and serum HDL-cholesterol level was found in women aged 30-45 years. There were no differences in indicators of insulin resistance between the groups. CONCLUSION: Insulin resistance was not shown to be a risk factor for fibroids. There is a negative association between some parameters of metabolic syndrome and fibroid volume.

Analysis of Risk Factors of Stroke and Venous Thromboembolism in Females With Oral Contraceptives Use.

Thrombotic diathesis has been a well-known complication of oral contraceptive use for more than 50 years. This is true not only for venous thrombosis but also for an arterial one. The etiology is usually multifactorial and depends on several additional risk factors. We analyzed the prevalence of inherited and acquired thrombophilia in a cohort of 770 females who had a thrombotic event in association with oral contraceptive use (700 women with venous thromboembolism [VTE], 70 with stroke). Moreover, we tried to identify additional risk factors. Inherited thrombophilia was found in 44.5% with higher frequency in the cohort with VTE (42%) than in females with stroke (24%). The most frequent finding was factor V Leiden. Cigarette smoking was significantly more frequent in the group with stroke (50% vs 25%). The prevalence of cigarette smoking in the group with VTE did not exceed the frequency in general population. Women on oral contraceptive pills have higher risk of venous as well as arterial thrombosis. The risk of venous thrombosis is increased in females with inherited thrombophilia, whereas those with some additional acquired risk factors (especially smoking) may be predisposed to arterial thrombosis. However, the absolute risk of thrombosis in healthy women is low, far less than the risk of unintended pregnancy. Moreover, the risk may be reduced by keeping some rules before the prescription of the pills, healthy life style, and a proper choice of contraception.

Rheopheresis in treatment of idiopathic sensorineural sudden hearing loss.

BACKROUND: Only few therapeutic options exist for patients with refractory sudden idiopathic sensorineural hearing loss (SISHL). Little is known about the efficacy of second-line therapies. Rheopheresis seems to be an effective therapeutic possibility. METHODS: Between 2012 and 2015, 106 patients with SISHL were enrolled in the study, of whom 52 were refractory to initial treatment. As salvage therapy, these patients were offered either 3 sessions of rheopheresis (33 pts) or intratympanic steroid treatment through MicroWick application (19 pts). Pure tone audiometry was performed at diagnosis, at the 1st month and the 1st year during the follow-up. RESULTS: Patients in the rheopheretic arm had higher hearing loss than in the MicroWick arm (81% vs. 52%, p = 0.04). In spite of this, there was a significant improvement for patients in the rheopheretic arm (27% of hearing loss reduction, p < 0.001) after the 1st month and this remained unchanged during the 1st year, while no improvement was seen in the MicroWick arm (0% of hearing loss reduction, p = 0.424). We found no predictive factor for steroid-failure in first-line therapy. Older age (p = 0.003), presence of vertigo (p = 0.006) and more profound initial hearing loss (p < 0.001) were identified as negative prognostic markers. CONCLUSION: Rheopheresis can be used as a potentially effective and safe salvage therapy for patients with cortico-refractory SISHL.

Dynamics of blood count after rheohemapheresis in age-related macular degeneration: possible association with clinical changes.

BACKGROUND: Rheohemapheresis (RHF) is a method that can stop the activity of the dry form of age-related macular degeneration (AMD). The pathophysiologic mechanisms are not well understood, and the effects of the RHF procedures extend beyond the time of the individual procedures. PATIENTS AND METHODS: We present the data for 46 patients with AMD treated with a series of 8 rheohemapheretic procedures. Blood count parameters were measured before the first and the last procedures. The clinical effect was judged by changes in the drusenoid pigment epithelium detachment (DPED) area before and after the rheopheretic sessions. RESULTS: Rheopheresis caused a decrease in hemoglobin (P<0.001), a decrease in leukocytes (P<0.034), and an increase in platelets (P<0.005). We found a negative correlation between the amount of platelets and their volume (P<0.001, Pearson correlation coefficient: -0.509). We identified the platelet/MPV ratio as a good predictor of the clinical outcome. Patients with a platelet/MPV ratio greater than 21.5 (before the last rheopheresis) had a significantly better outcome (P=0.003, sensitivity of 76.9% and specificity of 80%). CONCLUSION: Several basic blood count parameters after RHF can be concluded to significantly change, with some of those changes correlating with the clinical results (reduction of the DPED area).

The fetal splenic vein flow pattern and fetal inflammatory response in the preterm prelabor rupture of membranes.

OBJECTIVE: To evaluate the intensity of the fetal inflammatory response, characterized by umbilical cord blood IL-6 levels, and neonatal outcome in the preterm prelabor rupture of membranes (PPROM) pregnancies using the pulsatile fetal splenic vein flow pattern. METHODS: Women with singleton pregnancies complicated by PPROM at a gestational age between 24 + 0 and 36 + 6 weeks were included in the study. Doppler evaluation of the fetal splenic vein flow was performed. The flow-velocity waveform pattern was evaluated qualitatively as continuous or pulsatile. The umbilical cord blood interleukin-6 (IL-6) levels were evaluated after delivery. The fetal inflammatory response was defined as IL-6 >11 pg/mL. RESULTS: In total, 129 women were included. The fetuses with pulsatile splenic vein flow exhibited higher IL-6 levels in umbilical cord blood (median: 56.7 pg/mL versus 5.6 pg/mL; p < 0.0001) and had a higher rate of fetal inflammatory response syndrome (71% versus 35%; p = 0.0005) than fetuses with continuous flow. The pulsatile flow pattern was related to a higher rate of early onset neonatal sepsis (odds ratio 4.2; 95% confidence interval: 1.3-13.5). CONCLUSION: The presence of pulsatile fetal splenic vein flow in PPROM pregnancies is associated with fetal inflammatory response and neonatal morbidity.