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PROBLEM - Premature birth complicates 10%-12% of deliveries. Infection and inflammation are the most common etiologies and are associated with increased offspring morbidity and mortality. We hypothesize that lipopolysaccharide (LPS)-induced maternal inflammation causes direct placenta injury and subsequent injury to the fetal intestine.
METHOD OF STUDY - Pregnant C57Bl6 mice were injected intraperitoneally on day 15.5 with 100 μg/kg LPS or saline. Maternal serum, amniotic fluid, placental samples, and ileal samples of offspring were obtained assessed for inflammation and/or injury. Maternal placental ultrasounds were performed. Placental DNA was isolated for microbiome analysis.
RESULTS - Maternal injection with LPS caused elevated IL-1β, IL-10, IL-6, KC-GRO, and TNF. Placental tissue showed increased IL-1β, IL-6, and KC-GRO and decreased IL-10, but no changes were observed in amniotic fluid. Placental histology demonstrated LPS-induced increases in mineralization and necrosis, but no difference in placental blood flow. Most placentas had no detectable microbiome. Exposure to maternal LPS induced significant injury to the ilea of the offspring.
CONCLUSION - Lipopolysaccharide causes a maternal inflammatory response that is mirrored in the placenta. Placental histology demonstrates structural changes; however, placental blood flow is preserved. LPS also induces an indirect intestinal injury in the offspring that lasts beyond the neonatal period.
© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Zika virus (ZIKV) is an emerging mosquito-transmitted flavivirus that can cause severe disease, including congenital birth defects during pregnancy. To develop candidate therapeutic agents against ZIKV, we isolated a panel of human monoclonal antibodies from subjects that were previously infected with ZIKV. We show that a subset of antibodies recognize diverse epitopes on the envelope (E) protein and exhibit potent neutralizing activity. One of the most inhibitory antibodies, ZIKV-117, broadly neutralized infection of ZIKV strains corresponding to African and Asian-American lineages. Epitope mapping studies revealed that ZIKV-117 recognized a unique quaternary epitope on the E protein dimer-dimer interface. We evaluated the therapeutic efficacy of ZIKV-117 in pregnant and non-pregnant mice. Monoclonal antibody treatment markedly reduced tissue pathology, placental and fetal infection, and mortality in mice. Thus, neutralizing human antibodies can protect against maternal-fetal transmission, infection and disease, and reveal important determinants for structure-based rational vaccine design efforts.
PURPOSE - Between 1997 and 2002 a large number of fetal myelomeningocele closures were performed at our institution. Previously early reports showed little improvement in neonatal bladder function after fetal back closure. We evaluated the long-term urological impact of this procedure.
MATERIALS AND METHODS - Using a combination of retrospective review and survey questionnaire we reviewed the records of 28 patients in whom fetal myelomeningocele closure was done at our institution between 1997 and 2002. The areas addressed included medical management for neurogenic bladder and bowel, need for lower urinary tract reconstruction and functional bladder assessment by videourodynamics. Parameters after fetal myelomeningocele closure were compared to those of 33 age and sex matched patients with myelomeningocele who underwent standard postnatal closure.
RESULTS - We reviewed the records of 28 patients after fetal myelomeningocele closure. At a mean age of 9.6 years 23 used clean intermittent catheterization to manage the bladder, 24 required a bowel regimen to manage constipation and 6 underwent lower urinary tract reconstruction with enterocystoplasty and a catheterizable bladder channel. Videourodynamics performed in 14 patients at a mean age of 7.4 years revealed decreased bladder capacity in 71%, detrusor overactivity in 35% and increased detrusor pressure in 25%. Compared to age and sex matched children who underwent postnatal closure we noted no significant differences in bladder management, urinary tract surgery or urodynamics.
CONCLUSIONS - Neurogenic bowel and bladder management continues to be a significant issue for patients after fetal myelomeningocele closure. After fetal surgery patients should be followed closely, similar to patients who undergo postnatal closure.
Copyright © 2011 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.
OBJECTIVE - To summarize the state of research in maternal-fetal surgery regarding the surgical repair of abnormalities in fetuses in the womb.
DATA SOURCES - We searched MEDLINE from 1980 to 2010 for studies of maternal-fetal surgery for the following conditions: twin-twin transfusion syndrome, obstructive uropathy, congenital diaphragmatic hernia, myelomeningocele, thoracic lesions, cardiac malformations, and sacrococcygeal teratoma.
METHODS OF STUDY SELECTION - We used pilot-tested data collection forms to screen publications for inclusion and to extract data. We compiled information about how fetal diagnoses were defined, maternal inclusion criteria, type of surgery, study design, country, setting, comparators used, length of follow-up, outcomes measured, and adverse events.
TABULATION, INTEGRATION, AND RESULTS - Two reviewers independently extracted data and discordance was resolved by a third party. Of 1,341 articles located, we retained 258 (comprising 166 unique study populations). Three studies were randomized controlled trials; the majority of the evidence was observational (116 case series [70%], 36 retrospective [22%], and 11 prospective [7%] cohorts). Twin-twin transfusion is the most studied condition, with 84 studies including 2,532 pregnancies. Fewer than 500 pregnancies are represented in the literature for each of the other conditions except congenital diaphragmatic hernia (n=503). Inclusion criteria were poorly specified. Outcomes typically measured were survival to birth, preterm birth, and neonatal death. Longer-term outcomes were sparse but included pulmonary, renal, and neurologic status and developmental milestones. Maternal outcome data were rare.
CONCLUSION - Although developing rapidly, maternal-fetal surgery research has yet to achieve the typical quality of studies and aggregate strength of evidence needed to optimally inform care.
Gene targeting in the mouse has become a standard approach, yielding important new insights into the genetic factors underlying cardiovascular development and disease. However, we still have very limited understanding of how mutations affect developing cardiovascular function, and few studies have been performed to measure altered physiological parameters in mouse mutant embryos. Indeed, although in utero lethality due to embryonic heart failure is one of the most common results of gene targeting experiments in the mouse, the underlying physiological mechanisms responsible for embryonic demise remain elusive. Using in utero ultrasound biomicroscopy (UBM), we studied embryonic day (E) 10.5 to 14.5 NFATc1-/- embryos and control littermates. NFATc1-/- mice, which lack outflow valves, die at mid-late gestation from presumed defects in forward blood flow with resultant heart failure. UBM showed increasing abnormal regurgitant flow in the aorta and extending into the embryonal-placental circulation, which was evident after E12.5 when outflow valves normally first develop. Reduced NFATc1-/- net volume flow and diastolic dysfunction contributed to heart failure, but contractile function remained unexpectedly normal. Among 107 NFATc1-/- embryos imaged, only 2 were observed to be in acute decline with progressive bradyarrhythmia, indicating that heart failure occurs rapidly in individual NFATc1-/- embryos. This study is among the first linking a specific physiological phenotype with a defined genotype, and demonstrates that NFATc1-/- embryonic heart failure is a complex phenomenon not simply attributable to contractile dysfunction.
Erythropoietin (Epo) controls red cell production in the basal state and during stress. Epo binding to its receptor, EpoR, on erythroid progenitors leads to rapid activation of the transcription factor Stat5. Previously, fetal anemia and increased apoptosis of fetal liver erythroid progenitors were found in Stat5a(-/-)5b(-/-) mice. However, the role of Stat5 in adult erythropoiesis was not clear. The present study shows that some adult Stat5a(-/-)5b(-/-) mice have a near-normal hematocrit but are deficient in generating high erythropoietic rates in response to stress. Further, many adult Stat5a(-/-)5b(-/-) mice have persistent anemia despite a marked compensatory expansion in their erythropoietic tissue. Analysis of erythroblast maturation in Stat5a(-/-)5b(-/-) hematopoietic tissue shows a dramatic increase in early erythroblast numbers, but these fail to progress in differentiation. Decreased expression of bcl-x(L) and increased apoptosis in Stat5a(-/-)5b(-/-) early erythroblasts correlate with the degree of anemia. Hence, Stat5 controls a rate-determining step regulating early erythroblast survival.
Cyclooxygenase (COX)-derived prostaglandins (PGs) regulate numerous maternal-fetal interactions during pregnancy. PGs stimulate uterine contractions and prepare the cervix for parturition, whereas in the fetus, PGs maintain patency of the ductus arteriosus (DA), a vascular shunt that transmits oxygenated placental blood to the fetal systemic circulation. However, the origin and site of action of these PGs remain undefined. To address this, we analyzed mice lacking COX-1 (null mutation) or COX-2 (pharmacologic inhibition) or pups with a double null mutation. Our results show that COX-1 in the uterine epithelium is the major source of PGs during labor and that COX-1(-/-) females experience parturition failure that is reversible by exogenous PGs. Using embryo transfer experiments, we also show that successful delivery occurs in COX-1(-/-) recipient mothers carrying wild-type pups, establishing the sufficiency of fetal PGs for parturition. Although patency of the DA is PG dependent, neither COX-1 nor COX-2 expression was detected in the fetal or postnatal DA, and offspring with a double null mutation died shortly after birth with open DAs. These results suggest that DA patency depends on circulating PGs acting on specific PG receptors within the DA. Collectively, these findings demonstrate the coordinated regulation of fetal and maternal PGs at the time of birth but raise concern regarding the use of selective COX inhibitors for the management of preterm labor.
BACKGROUND - The increasing number of transgenic and targeted mutant mice with embryonic cardiac defects has resulted in the need for noninvasive techniques to examine cardiac structure and function in early mouse embryos. We report the first use of a novel 40-MHz ultrasound imaging system in the study of mouse cardiac development in utero.
METHODS AND RESULTS - Transabdominal scans of mouse embryos staged between 8.5 and 13.5 days of gestation (E8.5 to E13.5) were obtained in anesthetized mice. Atrial and ventricular contractions could be discerned from E9.5, and changes in cardiac morphology were observed from E9.5 to E13.5. Hyperechoic streaming patterns delineated flow through the umbilical, vitelline, and other major blood vessels. Diastolic and systolic ventricular areas were determined by planimetry of the epicardial borders, and fractional area change was measured as an index of contractile function. Significant increases in ventricular size were documented at each stage between E10.5 and E13.5, and the ability to perform serial imaging studies over 3 days of embryonic development is described. Finally, the detection of vascular cell adhesion molecule 1 (VCAM-1) homozygous null mutant embryos demonstrates the first example of noninvasive, in utero analysis of cardiac structure and function in a targeted mouse mutant.
CONCLUSIONS - We used 40-MHz echocardiography to identify key elements of the early mouse embryonic cardiovascular system and for noninvasive dimensional analysis of developing cardiac ventricles. The ability to perform serial measurements and to detect mutant embryos with cardiac defects highlights the usefulness of the technique for investigating normal and abnormal cardiovascular development.
A 36-year-old pregnant woman with anti-HPA1a antibodies underwent six fetal platelet concentrate transfusions. During the second, at 28 weeks' gestation, fetal asystole occurred in association with a post-transfusion platelet count of 813 x 10(9)/l. Asystole was reversed by an intracardiac partial exchange transfusion of normal saline for fetal blood, simultaneously reducing fetal plasma viscosity and enabling re-commencement of the fetal circulation.