RESUMO
OBJECTIVE: The study aimed to determine if a program of mid-trimester serum proteomics screening of women at low risk for spontaneous preterm birth (sPTB) and the use of a PTB risk-reduction protocol in those whose results indicated an increased risk of sPTB would reduce the likelihood of sPTB and its sequelae. STUDY DESIGN: Prospective comparison of birth outcomes in singleton pregnancies with mid-trimester cervical length ≥2.5 cm and at otherwise low risk for sPTB randomized to undergo or not undergo mid-trimester serum proteomics screening for increased risk of sPTB (NCT03530332). Screen-positive women were offered a group of interventions aimed at reducing the risk of spontaneous PTB. The primary outcome was the rate of sPTB <37 weeks, and secondary outcomes were gestational age at delivery, total length of neonatal stay, and NICU length of stay (LOS). Unscreened and screen-negative women received standard care. The adaptive study design targeted a sample size of 3,000 to 10,000 women to detect a reduction in sPTB from 6.4 to 4.7%. Due to limited resources, the trial was stopped early prior to data unblinding. RESULTS: A total of 1,191 women were randomized. Screened and unscreened women were demographically similar. sPTB <37 weeks occurred in 2.7% of screened women and 3.5% of controls (p = 0.41). In the screened compared with the unscreened group, there were no between-group differences in the gestational age at delivery, total length of neonatal stay, and NICU LOS. However, the NICU LOS among infants admitted for sPTB was significantly shorter (median = 6.8 days, interquartile range [IQR]: 1.8-8.0 vs. 45.5 days, IQR: 34.6-79.0; p = 0.005). CONCLUSION: Mid-trimester serum proteomics screening of women at low risk for sPTB and the use of a sPTB risk-reduction protocol in screen-positive patients did not significantly reduce the rate of sPTB compared with women not screened, though the trial was underpowered thus limiting the interpretation of negative findings. Infants in the screened group had a significantly shorter NICU LOS, a difference likely due to a reduced number of infants in the screened group that delivered <35 weeks. KEY POINTS: · Mid-trimester serum proteomics screening of women at low risk for sPTB and the use of a sPTB risk-reduction protocol in screen-positive patients did not significantly reduce the rate of sPTB, though the trial was underpowered.. · NICU LOS following sPTB was significantly shortened among women who underwent screening and risk-reduction management.. · The use of serum biomarkers may contribute to a practical strategy to reduce sPTB sequelae..
Assuntos
Nascimento Prematuro , Gravidez , Recém-Nascido , Humanos , Feminino , Nascimento Prematuro/prevenção & controle , Idade Gestacional , Projetos de Pesquisa , Colo do Útero/diagnóstico por imagem , Medida do Comprimento Cervical/métodosRESUMO
BACKGROUND: Preterm birth remains a common and devastating complication of pregnancy. There remains a need for effective and accurate screening methods for preterm birth. Using a proteomic approach, we previously discovered and validated (Proteomic Assessment of Preterm Risk study, NCT01371019) a preterm birth predictor comprising a ratio of insulin-like growth factor-binding protein 4 to sex hormone-binding globulin. OBJECTIVE: To determine the performance of the ratio of insulin-like growth factor-binding protein 4 to sex hormone-binding globulin to predict both spontaneous and medically indicated very preterm births, in an independent cohort distinct from the one in which it was developed. STUDY DESIGN: This was a prospective observational study (Multicenter Assessment of a Spontaneous Preterm Birth Risk Predictor, NCT02787213) at 18 sites in the United States. Women had blood drawn at 170/7 to 216/7 weeks' gestation. For confirmation, we planned to analyze a randomly selected subgroup of women having blood drawn between 191/7 and 206/7 weeks' gestation, with the results of the remaining study participants blinded for future validation studies. Serum from participants was analyzed by mass spectrometry. Neonatal morbidity and mortality were analyzed using a composite score by a method from the PREGNANT trial (NCT00615550, Hassan et al). Scores of 0-3 reflect increasing numbers of morbidities or length of neonatal intensive care unit stay, and 4 represents perinatal mortality. RESULTS: A total of 5011 women were enrolled, with 847 included in this planned substudy analysis. There were 9 preterm birth cases at <320/7 weeks' gestation and 838 noncases at ≥320/7 weeks' gestation; 21 of 847 infants had neonatal composite morbidity and mortality index scores of ≥3, and 4 of 21 had a score of 4. The ratio of insulin-like growth factor-binding protein 4 to sex hormone-binding globulin ratio was substantially higher in both preterm births at <320/7 weeks' gestation and there were more severe neonatal outcomes. The ratio of insulin-like growth factor-binding protein 4 to sex hormone-binding globulin ratio was significantly predictive of birth at <320/7 weeks' gestation (area under the receiver operating characteristic curve, 0.71; 95% confidence interval, 0.55-0.87; P=.016). Stratification by body mass index, optimized in the previous validation study (22
Assuntos
Nascimento Prematuro , Estudos de Coortes , Feminino , Idade Gestacional , Humanos , Recém-Nascido , Gravidez , Estudos Prospectivos , Proteômica , Estados UnidosRESUMO
BACKGROUND: Despite expectant management, preeclampsia remote from term usually results in preterm delivery. Antithrombin, which displays antiinflammatory and anticoagulant properties, may have a therapeutic role in treating preterm preeclampsia, a disorder characterized by endothelial dysfunction, inflammation, and activation of the coagulation system. OBJECTIVE: This randomized, placebo-controlled clinical trial aimed to evaluate whether intravenous recombinant human antithrombin could prolong gestation and therefore improve maternal and fetal outcomes. STUDY DESIGN: We performed a double-blind, placebo-controlled trial at 23 hospitals. Women were eligible if they had a singleton pregnancy, early-onset or superimposed preeclampsia at 23 0/7 to 30 0/7 weeks' gestation, and planned expectant management. In addition to standard therapy, patients were randomized to receive either recombinant human antithrombin 250 mg loading dose followed by a continuous infusion of 2000 mg per 24 hours or an identical saline infusion until delivery. The primary outcome was days gained from randomization until delivery. The secondary outcome was composite neonatal morbidity score. A total of 120 women were randomized. RESULTS: There was no difference in median gestational age at enrollment (27.3 weeks' gestation for the recombinant human antithrombin group [range, 23.1-30.0] and 27.6 weeks' gestation for the placebo group [range, 23.0-30.0]; P=.67). There were no differences in median increase in days gained (5.0 in the recombinant human antithrombin group [range, 0-75] and 6.0 for the placebo group [range, 0-85]; P=.95). There were no differences between groups in composite neonatal morbidity scores or in maternal complications. No safety issues related to recombinant human antithrombin were noted in this study, despite the achievement of supraphysiological antithrombin concentrations. CONCLUSION: The administration of recombinant human antithrombin in preterm preeclampsia neither prolonged pregnancy nor improved neonatal or maternal outcomes.
Assuntos
Proteínas Antitrombina/uso terapêutico , Cesárea/estatística & dados numéricos , Idade Gestacional , Pré-Eclâmpsia/tratamento farmacológico , Administração Intravenosa , Adolescente , Adulto , Parto Obstétrico/estatística & dados numéricos , Método Duplo-Cego , Feminino , Sofrimento Fetal/epidemiologia , Humanos , Doenças do Prematuro/epidemiologia , Recém-Nascido Pequeno para a Idade Gestacional , Pessoa de Meia-Idade , Sepse Neonatal/epidemiologia , Mortalidade Perinatal , Pré-Eclâmpsia/sangue , Pré-Eclâmpsia/fisiopatologia , Gravidez , Segundo Trimestre da Gravidez , Terceiro Trimestre da Gravidez , Estudos Prospectivos , Proteínas Recombinantes , Adulto JovemRESUMO
The rise of obesity among gravid women has been tracked and documented in many first-world countries, but a dramatic rise has been noted over the last 15 years. Definitions of "normal-weight, overweight and obese" have been defined; however, new terms are used to describe more severe degrees of obesity. Obesity in any form or degree increases morbidities in mothers. The unique physiologic characteristics of the obese gravida set up unique challenges in her management, especially in an acute setting such as labor. The definitions, trends, and management decisions pertaining to the obese parturient will be described in this review.
Assuntos
Obesidade , Complicações do Trabalho de Parto/terapia , Complicações na Gravidez , Índice de Massa Corporal , Tomada de Decisão Clínica , Feminino , Humanos , Obesidade/diagnóstico , Obesidade/fisiopatologia , Obesidade/terapia , Administração dos Cuidados ao Paciente/métodos , Gravidez , Complicações na Gravidez/diagnóstico , Complicações na Gravidez/fisiopatologia , Complicações na Gravidez/terapia , Resultado da GravidezRESUMO
BACKGROUND: Preterm delivery remains the leading cause of perinatal mortality. Risk factors and biomarkers have traditionally failed to identify the majority of preterm deliveries. OBJECTIVE: To develop and validate a mass spectrometry-based serum test to predict spontaneous preterm delivery in asymptomatic pregnant women. STUDY DESIGN: A total of 5501 pregnant women were enrolled between 17(0/7) and 28(6/7) weeks gestational age in the prospective Proteomic Assessment of Preterm Risk study at 11 sites in the United States between 2011 and 2013. Maternal blood was collected at enrollment and outcomes collected following delivery. Maternal serum was processed by a proteomic workflow, and proteins were quantified by multiple reaction monitoring mass spectrometry. The discovery and verification process identified 2 serum proteins, insulin-like growth factor-binding protein 4 (IBP4) and sex hormone-binding globulin (SHBG), as predictors of spontaneous preterm delivery. We evaluated a predictor using the log ratio of the measures of IBP4 and SHBG (IBP4/SHBG) in a clinical validation study to classify spontaneous preterm delivery cases (<37(0/7) weeks gestational age) in a nested case-control cohort different from subjects used in discovery and verification. Strict blinding and independent statistical analyses were employed. RESULTS: The predictor had an area under the receiver operating characteristic curve value of 0.75 and sensitivity and specificity of 0.75 and 0.74, respectively. The IBP4/SHBG predictor at this sensitivity and specificity had an odds ratio of 5.04 for spontaneous preterm delivery. Accuracy of the IBP4/SHBG predictor increased using earlier case-vs-control gestational age cutoffs (eg, <35(0/7) vs ≥35(0/7) weeks gestational age). Importantly, higher-risk subjects defined by the IBP4/SHBG predictor score generally gave birth earlier than lower-risk subjects. CONCLUSION: A serum-based molecular predictor identifies asymptomatic pregnant women at risk of spontaneous preterm delivery, which may provide utility in identifying women at risk at an early stage of pregnancy to allow for clinical intervention. This early detection would guide enhanced levels of care and accelerate development of clinical strategies to prevent preterm delivery.
Assuntos
Proteína 4 de Ligação a Fator de Crescimento Semelhante à Insulina/sangue , Nascimento Prematuro/sangue , Globulina de Ligação a Hormônio Sexual/análise , Biomarcadores/sangue , Feminino , Humanos , Espectrometria de Massas , Gravidez , Segundo Trimestre da Gravidez/sangue , Estudos Prospectivos , Curva ROC , Sensibilidade e EspecificidadeRESUMO
OBJECTIVE: Endogenous digitalis-like factors (EDLFs) are elevated in women with preeclampsia, and the use of an anti-digoxin antibody Fab (DIF) in women with preeclampsia who were remote from term reduced maternal blood pressure and preserved renal function. The objective was to determine whether DIF treatment in women with severe preeclampsia in association with positive EDLFs in maternal serum improves maternal-perinatal outcomes. STUDY DESIGN: This was a planned secondary analysis from a randomized, placebo-controlled, double-blind study of DIF in women with severe preeclampsia with positive EDLF status that was managed expectantly between 23 weeks 5 days and 34 weeks' gestation (19 women received placebo, and 17 women received DIF). Primary outcome variables were a change in creatinine clearance and the use of antihypertensives. Secondary outcomes were maternal and perinatal complications. RESULTS: Women with positive EDLFs who received DIF had an attenuated decline in creatinine clearance from baseline compared with placebo (-4.5 ± 12.9 vs -53.2 ± 12.6 mL/min; P = .005). In this same group, the use of antihypertensives (the other primary outcome) was lower but not significantly so (41% vs 63%; P = .12). However, women who were treated with DIF had a lower rate of pulmonary edema (1/17 vs 6/19 women; P = .035) and lower rates of neonatal intraventricular hemorrhage (DIF: 0/17 women vs placebo: 5/19 women; P = .015). CONCLUSION: In women with severe preeclampsia who were remote from term who were EDLF positive, the use of DIF was associated with improved maternal and neonatal outcome. These findings suggest the need for a large multicenter trial that would evaluate the benefits of DIF in the treatment of women with severe preeclampsia who are remote from term and with positive EDLF status.
Assuntos
Cardenolídeos/sangue , Fragmentos Fab das Imunoglobulinas/uso terapêutico , Pré-Eclâmpsia/tratamento farmacológico , Saponinas/sangue , Adulto , Anti-Hipertensivos/uso terapêutico , Creatinina/sangue , Método Duplo-Cego , Feminino , Humanos , Recém-Nascido , Pré-Eclâmpsia/sangue , GravidezRESUMO
We evaluated the efficacy, safety, and biological mechanisms of digoxin immune Fab (DIF) treatment of severe preeclampsia. Fifty-one severe preeclamptic patients were randomized in double-blind fashion to DIF ( N = 24) or placebo ( N = 27) for 48 hours. Primary outcomes were change in creatinine clearance (CrCl) at 24 to 48 hours and antihypertensive drug use. Serum sodium pump inhibition, a sequela of endogenous digitalis-like factors (EDLF), was also assessed. CrCl in DIF subjects was essentially unchanged from baseline versus a decrease with placebo (-3 +/- 10 and -34 +/- 10 mL/min, respectively, P = 0.02). Antihypertensive use was similar between treatments (46 and 52%, respectively, P = 0.7). Serum sodium pump inhibition was decreased with DIF compared with placebo at 24 hours after treatment initiation (least squares mean difference, 19 percentage points, P = 0.03). DIF appeared to be well tolerated. These results suggest DIF prevents a decline in renal function in severe preeclampsia by neutralizing EDLF. Sodium pump inhibition was significantly improved. Further research is warranted.
Assuntos
Anti-Hipertensivos/administração & dosagem , Fragmentos Fab das Imunoglobulinas/administração & dosagem , Pré-Eclâmpsia/tratamento farmacológico , Adulto , Anti-Hipertensivos/efeitos adversos , Cardenolídeos/sangue , Digoxina/imunologia , Método Duplo-Cego , Feminino , Humanos , Fragmentos Fab das Imunoglobulinas/análise , Testes de Função Renal , Pré-Eclâmpsia/sangue , Pré-Eclâmpsia/diagnóstico , Pré-Eclâmpsia/fisiopatologia , Gravidez , Resultado da Gravidez , Saponinas/sangue , ATPase Trocadora de Sódio-Potássio/antagonistas & inibidores , Resultado do Tratamento , Adulto JovemRESUMO
UNLABELLED: Multiple factors account for the increasing number of cesarean delivery wound complications in the United States; among them are an increase in cesarean delivery and an increase in the number of overweight and obese patients. This article reviews the pathophysiology of acute wound healing. Risk factors for cesarean delivery wound complications are identified and described. Clinical practices that can reduce the risk of developing wound complications, including Centers for Disease Control and Prevention guidelines, are considered. Treatment guidelines to accelerate wound healing such as secondary closure and negative pressure wound therapy in disrupted wounds are proposed. Older guidelines for management of wounds using secondary intention are critiqued. Historical methods of wound care such as the practice of using certain cleansers and the practice of wet to dry dressings are outdated. Modern wound healing products are described. TARGET AUDIENCE: Obstetricians & Gynecologists, Family Physicians LEARNING OBJECTIVES: After completion of this article, the reader should be able to describe the effects of obesity on cesarean delivery wound healing, to improve methods of wound healing in the obese patient, and to explain why wet to dry dressing changes are not effective wound management.
Assuntos
Cesárea/efeitos adversos , Deiscência da Ferida Operatória/terapia , Infecção da Ferida Cirúrgica/terapia , Cicatrização/fisiologia , Feminino , Humanos , Obesidade/complicações , Gravidez , Fatores de Risco , Deiscência da Ferida Operatória/etiologia , Deiscência da Ferida Operatória/fisiopatologia , Infecção da Ferida Cirúrgica/etiologia , Infecção da Ferida Cirúrgica/fisiopatologiaRESUMO
OBJECTIVE: The study was undertaken to exhibit and quantify the difference in modulation of CD3-zeta protein (an integral component of the T-cell receptor) in preeclamptic and normotensive women. STUDY DESIGN: Serum was collected from 10 preeclamptic and 10 normotensive women at >or=37 weeks' gestation on admission. Jurkat E-61 cells were incubated with the sera (20% volume to volume) and analyzed with Western immunoblot using mouse monoclonal CD3-zeta antibody. Enhanced chemiluminescence and densitometry were used to qualitatively measure zeta expression of the cells. A de novo flow cytometry assay was developed to quantify the difference in CD3-zeta expression of these cells. Comparisons were performed by t test (P<.05 was significant). RESULTS: Preeclamptic patient sera produced a 2.4-fold increase in CD3-zeta expression than normotensive patients on Western blot (P<.01). Flow cytometry showed that preeclamptic sera had a 1.4-fold higher expression of CD3-zeta compared with normotensive patients (P<.0003). CONCLUSION: TcR/CD3-zeta expression is normally suppressed in pregnancy. Loss of this suppression occurs in preeclamptic patients, implying increased T-cell function.
Assuntos
Complexo CD3/análise , Pré-Eclâmpsia/imunologia , Complexo Receptor-CD3 de Antígeno de Linfócitos T/análise , Adulto , Anticorpos Monoclonais , Western Blotting , Feminino , Citometria de Fluxo , Idade Gestacional , Humanos , Medições Luminescentes , GravidezRESUMO
OBJECTIVE: We examined whether mononuclear cell purification of human blood could be done while minimizing contamination with RhD-positive red blood cells to treat hemolytic disease of the fetus/newborn that was caused by rhesus disease. STUDY DESIGN: Whole blood from 16 individuals who tested rhesus positive was diluted and centrifuged over a Ficoll gradient. The cell pellet was incubated with red blood cell lysis buffer, divided into three samples, and analyzed for cell count, mononuclear cell yield, and RhD-positive red cell contamination by flow cytometry. RESULTS: Mean RhD-positive red cell contamination was 0.24% (range, 0%-1.9%). The average yield of mononuclear cells was 11.5% (range, 1.8%-23.6%). Through regression analysis, 34 to 180 mL of paternal whole blood would be necessary to achieve an antigen load that is sufficient for an HLA antibody response. CONCLUSION: Purification of human blood is possible to produce reasonable mononuclear cell yields with minimal rhesus activity, which makes paternal leukocyte therapy a plausible treatment for severe rhesus alloimmunization.
Assuntos
Remoção de Componentes Sanguíneos/métodos , Eritroblastose Fetal/terapia , Eritrócitos , Leucócitos Mononucleares/transplante , Contagem de Eritrócitos , Eritrócitos/imunologia , Feminino , Citometria de Fluxo , Humanos , Recém-Nascido , Gravidez , Isoimunização Rh/terapiaRESUMO
Our objective was to identify shed placental plasma membrane fragments in the maternal circulation and determine whether these fragments are capable of down-regulating CD3-zeta chain expression and inducing apoptosis in T lymphocytes. Sera, isolated from the blood of pregnant women at 26-29 weeks gestation that subsequently had uncomplicated term deliveries, were subjected to high exclusion-limit gel chromatography to isolate placental membrane fragments. The placental origin of the fragments was confirmed by the presence of placental-type alkaline phosphates. These shed membrane fragments were further analyzed for the presence of Fas ligand (FasL) and modulation of CD3-zeta expression on cultured T-lymphocytes (Jurkat cells). The ability of the shed membrane fragments to induce apoptosis was assayed using a cell death ELISA. Components associated with Fas-dependent apoptosis (caspase-3, bcl-2 and bax) were characterized using western immunoblot following exposure to serum-derived membrane fragments. Placental membrane fragments were identified in all pregnancy sera, but not in non-pregnant controls. The 41 kDa FasL was identified in membrane fragment isolates and all samples were capable of inducing apoptosis as determined by the ELISA assay. Exposure of T lymphocytes to isolated membrane fragments suppressed the expression of CD3-zeta. The induction of apoptosis correlated with the induction and activation of caspase 3 and the induction of bax. Placenta-derived membrane fragments are detectable in the maternal circulation. These membrane fragment isolates are capable of inducing FasL-mediated apoptosis and down-regulating CD3-zeta expression, which may contribute to the immune tolerance of the fetus.