ABSTRACT
BACKGROUND: Twin anemia polycythemia sequence is a chronic form of unbalanced fetofetal transfusion through minuscule placental anastomoses in monochorionic twins, leading to anemia in the donor and polycythemia in the recipient. Owing to the low incidence of twin anemia polycythemia sequence, data on diagnosis, management, and outcome are limited. OBJECTIVE: This study aimed to investigate the diagnosis, management, and outcome in a large international cohort of spontaneous twin anemia polycythemia sequence. STUDY DESIGN: Data from the international twin anemia polycythemia sequence registry, retrospectively collected between 2014 and 2019, were used for this study. A total of 17 fetal therapy centers contributed to the data collection. The primary outcomes were perinatal mortality and severe neonatal morbidity. Secondary outcomes included a risk factor analysis for perinatal mortality and severe neonatal morbidity. RESULTS: A total of 249 cases of spontaneous twin anemia polycythemia sequence were included in this study, 219 (88%) of which were diagnosed antenatally and 30 (12%) postnatally. Twin anemia polycythemia sequence was diagnosed antenatally at a median gestational age of 23.7 weeks (interquartile range, 9.7-28.8; range, 15.1-35.3). Antenatal management included laser surgery in 39% (86 of 219), expectant management in 23% (51 of 219), delivery in 16% (34 of 219), intrauterine transfusion (with partial exchange transfusion) in 12% (26 of 219), selective feticide in 8% (18 of 219), and termination of pregnancy in 1% (3 of 219) of cases. Perinatal mortality rate was 15% (72 of 493) for the total group, 22% (54 of 243) for donors, and 7% (18 of 242) for recipients (P<.001). Severe neonatal morbidity occurred in 33% (141 of 432) of twins with twin anemia polycythemia sequence and was similar for donors (32%; 63 of 196) and recipients (33%; 75 of 228) (P=.628). Independent risk factors for spontaneous perinatal mortality were donor status (odds ratio, 3.8; 95% confidence interval, 1.9-7.5; P<.001), antenatal twin anemia polycythemia sequence stage (odds ratio, 6.3; 95% confidence interval, 1.4-27.8; P=.016 [stage 2]; odds ratio, 9.6; 95% confidence interval, 2.1-45.5; P=.005 [stage 3]; odds ratio, 20.9; 95% confidence interval, 3.0-146.4; P=.002 [stage 4]), and gestational age at birth (odds ratio, 0.8; 95% confidence interval, 0.7-0.9; P=.001). Independent risk factors for severe neonatal morbidity were antenatal twin anemia polycythemia sequence stage 4 (odds ratio, 7.9; 95% confidence interval, 1.4-43.3; P=.018) and gestational age at birth (odds ratio, 1.7; 95% confidence interval, 1.5-2.1, P<.001). CONCLUSION: Spontaneous twin anemia polycythemia sequence can develop at any time in pregnancy from the beginning of the second trimester to the end of the third trimester. Management for twin anemia polycythemia sequence varies considerably, with laser surgery being the most frequent intervention. Perinatal mortality and severe neonatal morbidity were high, the former especially so in the donor twins.
Subject(s)
Blood Transfusion, Intrauterine , Fetal Therapies , Fetofetal Transfusion/therapy , Gestational Age , Laser Therapy , Perinatal Mortality , Watchful Waiting , Abortion, Induced , Anemia/diagnosis , Anemia/therapy , Birth Weight , Cerebral Infarction/epidemiology , Cerebral Intraventricular Hemorrhage/epidemiology , Cohort Studies , Delivery, Obstetric , Ductus Arteriosus, Patent/epidemiology , Ductus Arteriosus, Patent/therapy , Enterocolitis, Necrotizing/epidemiology , Female , Fetal Growth Retardation/epidemiology , Fetofetal Transfusion/diagnosis , Humans , Infant, Newborn , Internationality , Leukomalacia, Periventricular/epidemiology , Male , Polycythemia/diagnosis , Polycythemia/therapy , Pregnancy , Pregnancy Reduction, Multifetal , Pulmonary Surfactants/therapeutic use , Respiration, Artificial , Respiratory Distress Syndrome, Newborn/epidemiology , Respiratory Distress Syndrome, Newborn/therapy , Retinopathy of Prematurity/epidemiology , Risk Factors , Severity of Illness IndexABSTRACT
BACKGROUND: To improve neonatal outcomes in pregnancies at heightened risk for early-onset neonatal sepsis (EONS), there is a need to identify fetuses that benefit from expectant management as opposed to early delivery. Detectable haptoglobin and haptoglobin-related protein (Hp&HpRP switch-on status) in cord blood has been proposed as a biomarker of antenatal exposure to intra-amniotic infection and/or inflammation (IAI), an important determinant of EONS. SUBJECTS AND METHODS: We analyzed 185 singleton newborns delivered secondary to preterm premature rupture of membranes (PPROM). In 123 cases, amniocentesis was performed to exclude amniotic fluid (AF) infection. Delivery was indicated for 61 cases with confirmed infection. Women without AF infection (n = 62) and those without amniocentesis (n = 62) were managed expectantly. Interleukin 6 and Hp&HpRP switch-on status were evaluated by ELISA and Western blot. Newborns were followed prospectively for short-term outcomes until hospital discharge or death. RESULTS: Newborns exposed antenatally to IAI had an increased risk of adverse neonatal outcome [OR: 3.0 (95% CI: 1.15-7.59)]. Increasing gestational age [OR: 0.61 (95% CI: 0.52-0.70)] and management with amniocentesis [OR: 0.37 (95% CI: 0.14-0.95)] lowered the newborn's risk of developing adverse outcomes. DISCUSSION: In the setting of PPROM and IAI, early delivery benefits a select subgroup of fetuses that have not yet progressed to Hp&HpRP switch-on status.
Subject(s)
Amniotic Fluid/microbiology , Infections/etiology , Adult , Amniotic Fluid/metabolism , Antigens, Neoplasm/metabolism , Delivery, Obstetric , Female , Fetal Blood/metabolism , Fetal Membranes, Premature Rupture/metabolism , Fetal Membranes, Premature Rupture/microbiology , Fetal Membranes, Premature Rupture/therapy , Gestational Age , Haptoglobins/metabolism , Humans , Infant, Newborn , Infections/metabolism , Infections/microbiology , Pregnancy , Pregnancy Outcome , Premature Birth , Prospective Studies , Young AdultABSTRACT
BACKGROUND: The arsenal of maternal and amniotic fluid (AF) immune response to local or systemic infection includes among others the acute-phase reactants IL-6, C-Reactive Protein (CRP) and Procalcitonin (PCT). If these molecules can be used as non-invasive biomarkers of intra-amniotic infection (IAI) in the subclinical phase of the disease remains incompletely known. METHODS: We used time-matched maternal serum, urine and AF from 100 pregnant women who had an amniocentesis to rule out IAI in the setting of preterm labor, PPROM or systemic inflammatory response (SIR: pyelonephritis, appendicitis, pneumonia) to infection. Cord blood was analyzed in a subgroup of cases. We used sensitive immunoassays to quantify the levels of inflammatory markers in the maternal blood, urine and AF compartment. Microbiological testing and placental pathology was used to establish infection and histological chorioamnionitis. RESULTS: PCT was not a useful biomarker of IAI in any of the studied compartments. Maternal blood IL-6 and CRP levels were elevated in women with subclinical IAI. Compared to clinically manifest chorioamnionitis group, women with SIR have higher maternal blood IL-6 levels rendering some marginal diagnostic benefit for this condition. Urine was not a useful biological sample for assessment of IAI using either of these three inflammatory biomarkers. CONCLUSIONS: In women with subclinical IAI, the large overlapping confidence intervals and different cut-offs for the maternal blood levels of IL-6, CRP and PCT likely make interpretation of their absolute values difficult for clinical decision-making.
Subject(s)
C-Reactive Protein/analysis , Calcitonin/analysis , Chorioamnionitis/diagnosis , Interleukin-6/analysis , Protein Precursors/analysis , Adult , Amniocentesis , Amniotic Fluid/chemistry , Amniotic Fluid/microbiology , Asymptomatic Infections , Biomarkers/blood , Biomarkers/urine , C-Reactive Protein/urine , Calcitonin/blood , Calcitonin/urine , Calcitonin Gene-Related Peptide , Chorioamnionitis/microbiology , Female , Fetal Blood/immunology , Fetal Membranes, Premature Rupture , Humans , Infant, Newborn , Interleukin-6/blood , Interleukin-6/urine , Obstetric Labor, Premature , Placenta/pathology , Pregnancy , Pregnancy Complications, Infectious/immunology , Premature Birth , Protein Precursors/blood , Protein Precursors/urine , Systemic Inflammatory Response SyndromeABSTRACT
Classic IL-6 signaling is conditioned by the transmembrane receptor (IL-6R) and homodimerization of gp130. During trans-signaling, IL-6 binds to soluble IL-6R (sIL-6R), enabling activation of cells expressing solely gp130. Soluble gp130 (sgp130) selectively inhibits IL-6 trans-signaling. To characterize amniotic fluid (AF) IL-6 trans-signaling molecules (IL-6, sIL-6R, sgp130) in normal gestations and pregnancies complicated by intra-amniotic inflammation (IAI), we studied 301 women during second trimester (n = 39), third trimester (n = 40), and preterm labor with intact (n = 131, 85 negative IAI and 46 positive IAI) or preterm premature rupture of membranes (PPROM; n = 91, 61 negative IAI and 30 positive IAI). ELISA, Western blotting, and real-time RT-PCR were used to investigate AF, placenta, and amniochorion for protein and mRNA expression of sIL-6R, sgp130, IL-6R, and gp130. Tissues were immunostained for IL-6R, gp130, CD15(+) (polymorphonuclear), and CD3(+) (T cell) inflammatory cells. The ability of sIL-6R and sgp130 to modulate basal and LPS-stimulated release of amniochorion matrix metalloprotease-9 was tested ex vivo. We showed that in physiologic gestations, AF sgp130 decreases toward term. AF IL-6 and sIL-6R were increased in IAI, whereas sgp130 was decreased in PPROM. Our results suggested that fetal membranes are the probable source of AF sIL-6R and sgp130. Immunohistochemistry and RT-PCR revealed increased IL-6R and decreased gp130 expression in amniochorion of women with IAI. Ex vivo, sIL-6R and LPS augmented amniochorion matrix metalloprotease-9 release, whereas sgp130 opposed this effect. We conclude that IL-6 trans-signaling molecules are physiologic constituents of the AF regulated by gestational age and inflammation. PPROM likely involves functional loss of sgp130.
Subject(s)
Amniotic Fluid/immunology , Fetal Membranes, Premature Rupture/immunology , Inflammation Mediators/physiology , Interleukin-6/physiology , Pregnancy Complications/immunology , Premature Birth/immunology , Signal Transduction/immunology , Adult , Amniocentesis , Amniotic Fluid/enzymology , Amniotic Fluid/metabolism , Cytokine Receptor gp130/physiology , Female , Fetal Membranes, Premature Rupture/enzymology , Fetal Membranes, Premature Rupture/pathology , Humans , Infant, Newborn , Infant, Premature , Inflammation Mediators/antagonists & inhibitors , Inflammation Mediators/metabolism , Interleukin-6/antagonists & inhibitors , Interleukin-6/metabolism , Matrix Metalloproteinase 9/metabolism , Matrix Metalloproteinase Inhibitors , Pregnancy , Pregnancy Complications/enzymology , Pregnancy Complications/pathology , Premature Birth/enzymology , Premature Birth/pathology , Receptors, Interleukin-6/antagonists & inhibitors , Receptors, Interleukin-6/physiology , Young AdultABSTRACT
It is known that the rate of caesarean section (C-section) has been increasing among preterm births. However, the relationship between C-section and long-term neurological outcomes is unclear. In this study, we utilized diffusion tensor imaging (DTI) to characterize the association of delivery method with brain white matter (WM) microstructural integrity in preterm infants. We retrospectively analyzed the DTI scans and health records of preterm infants without neuroimaging abnormality on pre-discharge term-equivalent MRI. We applied both voxel-wise and tract-based analyses to evaluate the association between delivery method and DTI metrics across WM tracts while controlling for numerous covariates. We included 68 preterm infants in this study (23 delivered vaginally, 45 delivered via C-section). Voxel-wise and tract-based analyses revealed significantly lower fractional anisotropy values and significantly higher diffusivity values across major WM tracts in preterm infants delivered via C-section when compared to those delivered vaginally. These results may be partially, but not entirely, mediated by lower birth weight among infants delivered by C-section. Nevertheless, these infants may be at risk for delayed neurodevelopment and could benefit from close neurological follow up for early intervention and mitigation of adverse long-term outcomes.
ABSTRACT
It is known that the rate of caesarean section (C-section) has been increasing among preterm births. However, the relationship between C-section and long-term neurological outcomes is unclear. In this study, we utilized diffusion tensor imaging (DTI) to characterize the association of delivery method with brain white matter (WM) microstructural integrity in preterm infants. We retrospectively analyzed the DTI scans and health records of preterm infants without neuroimaging abnormality on pre-discharge term-equivalent MRI. We applied both voxel-wise and tract-based analyses to evaluate the association between delivery method and DTI metrics across WM tracts while controlling for numerous covariates. We included 68 preterm infants in this study (23 delivered vaginally, 45 delivered via C-section). Voxel-wise and tract-based analyses revealed significantly lower fractional anisotropy values and significantly higher diffusivity values across major WM tracts in preterm infants delivered via C-section when compared to those delivered vaginally. These results may be partially, but not entirely, mediated by lower birth weight among infants delivered by C-section. Nevertheless, these infants may be at risk for delayed neurodevelopment and could benefit from close neurological follow up for early intervention and mitigation of adverse long-term outcomes.
Subject(s)
Infant, Premature , White Matter , Pregnancy , Infant , Humans , Infant, Newborn , Female , Diffusion Tensor Imaging/methods , Brain/diagnostic imaging , Cesarean Section , Retrospective Studies , White Matter/diagnostic imagingABSTRACT
Prior research has shown that urine of women with preeclampsia (PE) contains amyloid-like aggregates that are congophilic (exhibit affinity for the amyloidophilic dye Congo red) and immunoreactive with A11, a polyclonal serum against prefibrillar ß-amyloid oligomers, thereby supporting pathogenic similarity between PE and protein conformational disorders such as Alzheimer's and prion disease. The objective of this study was to interrogate PE urine using monoclonal antibodies with previously characterized A11-like epitopes. Over 100 conformation-dependent monoclonals were screened and three (mA11-09, mA11-89, and mA11-205) selected for further confirmation in 196 urine samples grouped as follows: severe features PE (sPE, n = 114), PE without severe features (mPE, n = 30), chronic hypertension (crHTN, n = 14) and normotensive pregnant control (P-CRL, n = 38). We showed that the selected conformation-specific monoclonals distinguished among patients with varying severities of PE from P-CRL and patients with crHTN. By use of latent class analysis (LCA) we identified three classes of subjects: Class 1 (n = 94) comprised patients whose urine was both congophilic and reactive with the monoclonals. These women were more likely diagnosed with early-onset sPE and had severe hypertension and proteinuria; Class 2 patients (n = 55) were negative for congophilia and against the antibodies. These were predominantly P-CRL and crHTN patients. Lastly, Class 3 patients (n = 48) were positive for urine congophilia, albeit at lower intensity, but negative for monoclonal immunoreactivities. These women were diagnosed primarily as mPE or late-onset sPE. Collectively, our study validates conformation-dependent Aß imunoreactivity of PE urine which in conjunction to urine congophilia may represent an additional indicator of disease severity.
Subject(s)
Hypertension , Pre-Eclampsia , Antibodies, Monoclonal , Congo Red , Female , Humans , Pre-Eclampsia/metabolism , Pregnancy , ProteinuriaABSTRACT
OBJECTIVE: We sought to characterize serum angiogenic factor profile of women with complete placenta previa and determine if invasive trophoblast differentiation characteristic of accreta, increta, or percreta shares features of epithelial-to-mesenchymal transition. STUDY DESIGN: We analyzed gestational age-matched serum samples from 90 pregnant women with either complete placenta previa (n = 45) or uncomplicated pregnancies (n = 45). Vascular endothelial growth factor (VEGF), placental growth factor, and soluble form of fms-like-tyrosine-kinase-1 were immunoassayed. VEGF and phosphotyrosine immunoreactivity was surveyed in histological specimens relative to expression of vimentin and cytokeratin-7. RESULTS: Women with previa and invasive placentation (accreta, n = 5; increta, n = 6; percreta, n = 2) had lower systemic VEGF (invasive previa: median 0.8 [0.02-3.4] vs control 6.5 [2.7-10.5] pg/mL, P = .02). VEGF and phosphotyrosine immunostaining predominated in the invasive extravillous trophoblasts that coexpressed vimentin and cytokeratin-7, an epithelial-to-mesenchymal transition feature and tumorlike cell phenotype. CONCLUSION: Lower systemic free VEGF and a switch of the interstitial extravillous trophoblasts to a metastable cell phenotype characterize placenta previa with excessive myometrial invasion.
Subject(s)
Placenta Accreta/metabolism , Placenta Previa/metabolism , Trophoblasts/metabolism , Vascular Endothelial Growth Factor A/metabolism , Adult , Case-Control Studies , Epithelial-Mesenchymal Transition , Female , Humans , Keratin-7/metabolism , Phosphotyrosine/metabolism , Placenta Accreta/pathology , Placenta Growth Factor , Placenta Previa/pathology , Pregnancy , Pregnancy Proteins/blood , Trophoblasts/pathology , Vascular Endothelial Growth Factor Receptor-1/blood , Vimentin/metabolismABSTRACT
OBJECTIVE: The aim of this study was to determine whether sonographic fetal pulmonary artery flow velocity waveforms correlate with amniotic fluid biomarkers of fetal lung maturity. STUDY DESIGN: We studied women with singleton pregnancies undergoing clinically indicated amniocentesis for fetal lung maturity at Yale-New Haven Hospital. Fetal pulmonary artery flow velocity measurements, including systolic/diastolic ratio, pulsatility index, resistance index, and acceleration-time/ejection-time ratio were obtained using spectral Doppler ultrasound. Pearson's correlation coefficient was used to determine the association between fetal pulmonary artery flow velocity parameters and the lecithin/sphingomyelin ratio. RESULTS: Twenty-nine subjects met study criteria. The acceleration-time/ejection-time ratio was inversely correlated with the lecithin/sphingomyelin ratio (r = -0.76; P < or = .001). This relationship was maintained after controlling for potential confounders. Other fetal pulmonary artery flow velocity measurements were not associated with the lecithin/sphingomyelin ratio. CONCLUSION: There is an inverse correlation between the acceleration-time/ejection-time ratio in the fetal pulmonary artery and the amniotic fluid lecithin/sphingomyelin ratio. This suggests that ultrasound evaluation of fetal pulmonary artery blood flow may be a promising new noninvasive technique to evaluate fetal lung maturity.
Subject(s)
Fetal Organ Maturity/physiology , Lung/diagnostic imaging , Pulmonary Artery/diagnostic imaging , Respiratory Distress Syndrome, Newborn/diagnostic imaging , Ultrasonography, Prenatal/methods , Adult , Amniotic Fluid/metabolism , Blood Flow Velocity/physiology , Cohort Studies , Female , Fetus , Humans , Infant, Newborn , Lung/blood supply , Lung/physiology , Male , Phosphatidylcholines/metabolism , Pregnancy , Pulmonary Artery/embryology , Respiratory Distress Syndrome, Newborn/metabolism , Sphingomyelins/metabolism , Statistics, NonparametricABSTRACT
The aim of this study was to investigate the management and outcome in the post-laser twin anemia polycythemia sequence (TAPS). Data of the international TAPS Registry, collected between 2014 and 2019, were used for this study. The primary outcomes were perinatal mortality and severe neonatal morbidity. Secondary outcomes included a risk factor analysis for perinatal mortality and severe neonatal morbidity. A total of 164 post-laser TAPS pregnancies were included, of which 92% (151/164) were diagnosed antenatally and 8% (13/164) postnatally. The median number of days between laser for TTTS and detection of TAPS was 14 (IQR: 7-28, range: 1-119). Antenatal management included expectant management in 43% (62/151), intrauterine transfusion with or without partial exchange transfusion in 29% (44/151), repeated laser surgery in 15% (24/151), selective feticide in 7% (11/151), delivery in 6% (9/151), and termination of pregnancy in 1% (1/151). The median gestational age (GA) at birth was 31.7 weeks (IQR: 28.6-33.7; range: 19.0-41.3). The perinatal mortality rate was 25% (83/327) for the total group, 37% (61/164) for donors, and 14% (22/163) for recipients (p < 0.001). Severe neonatal morbidity was detected in 40% (105/263) of the cohort and was similar for donors (43%; 51/118) and recipients (37%; 54/145), p = 0.568. Independent risk factors for spontaneous perinatal mortality were antenatal TAPS Stage 4 (OR = 3.4, 95%CI 1.4-26.0, p = 0.015), TAPS donor status (OR = 4.2, 95%CI 2.1-8.3, p < 0.001), and GA at birth (OR = 0.8, 95%CI 0.7-0.9, p = 0.001). Severe neonatal morbidity was significantly associated with GA at birth (OR = 1.5, 95%CI 1.3-1.7, p < 0.001). In conclusion, post-laser TAPS most often occurs within one month after laser for TTTS, but may develop up to 17 weeks after initial surgery. Management is mostly expectant, but varies greatly, highlighting the lack of consensus on the optimal treatment and heterogeneity of the condition. Perinatal outcome is poor, particularly due to the high rate of perinatal mortality in donor twins.
ABSTRACT
OBJECTIVE: The objective of the study was to evaluate the fetal renal artery impedance in the context of inflammation-associated preterm birth. STUDY DESIGN: We conducted a prospective Doppler assessment of the fetal renal artery impedance in 70 singleton fetuses. The study group consisted of 56 premature fetuses (median, 28.1 [interquartile range, 25.3-30.6] weeks at enrollment). Gestational age (GA) reference ranges were generated based on fetuses with uncomplicated pregnancies (n = 14). Doppler studies included renal artery pulsatility index (PI), resistance index (RI), systolic/diastolic (S/D) ratio, and presence or absence of end-diastolic blood flow. Proteomic profiling (surface-enhanced laser desorption ionization time-of-flight) was used for assessment of intraamniotic inflammation and biomarker peak corresponding to beta2-microglubin. Data were interpreted in relationship to amniotic fluid index (AFI), cord blood interleukin (IL)-6 and erythropoietin (EPO) levels. The cardiovascular and metabolic profiles of the neonates were investigated in the first 24 hours of life. RESULTS: Fetuses delivered by mothers with intraamniotic inflammation had higher cord blood IL-6 but not EPO levels. Fetal inflammation did not affect either renal artery PI, RI, S/D ratio, or end-diastolic blood flow. Neonates delivered in the context of intraamniotic inflammation had higher serum blood urea nitrogen levels, which correlated significantly with AF IL-6 levels. The renal artery RI and SD ratio were inversely correlated with the AFI independent of GA, cord blood IL-6, and status of the membranes. CONCLUSION: The fetus is capable of sustaining normal renal artery impedance despite inflammation. Resistance in the renal vascular bed affects urine output independent of inflammation.
Subject(s)
Amniotic Fluid/immunology , Renal Artery/diagnostic imaging , Vascular Resistance/immunology , Adult , Amniocentesis , Female , Fetal Membranes, Premature Rupture/immunology , Fetus , Hemodynamics , Humans , Infant, Newborn , Infant, Premature , Obstetric Labor, Premature/immunology , Pregnancy , Premature Birth/immunology , Prospective Studies , Renal Artery/immunology , Ultrasonography, Doppler , Young AdultABSTRACT
INTRODUCTION: Twin-to-twin transfusion syndrome (TTTS) is a potentially lethal condition that affects pregnancies in which twins share a single placenta. The definitive treatment for TTTS is fetoscopic laser photocoagulation, a procedure in which placental blood vessels are selectively cauterized. Challenges in this procedure include difficulty in quickly identifying placental blood vessels due to the many artifacts in the endoscopic video that the surgeon uses for navigation. We propose using deep-learned segmentations of blood vessels to create masks that can be recombined with the original fetoscopic video frame in such a way that the location of placental blood vessels is discernable at a glance. METHODS: In a process approved by an institutional review board, intraoperative videos were acquired from ten fetoscopic laser photocoagulation surgeries performed at Yale New Haven Hospital. A total of 345 video frames were selected from these videos at regularly spaced time intervals. The video frames were segmented once by an expert human rater (a clinician) and once by a novice, but trained human rater (an undergraduate student). The segmentations were used to train a fully convolutional neural network of 25 layers. RESULTS: The neural network was able to produce segmentations with a high similarity to ground truth segmentations produced by an expert human rater (sensitivity = 92.15% ± 10.69%) and produced segmentations that were significantly more accurate than those produced by a novice human rater (sensitivity = 56.87% ± 21.64%; p < 0.01). CONCLUSION: A convolutional neural network can be trained to segment placental blood vessels with near-human accuracy and can exceed the accuracy of novice human raters. Recombining these segmentations with the original fetoscopic video frames can produced enhanced frames in which blood vessels are easily detectable. This has significant implications for aiding fetoscopic surgeons-especially trainees who are not yet at an expert level.
Subject(s)
Deep Learning , Fetofetal Transfusion/surgery , Fetoscopy/methods , Image Processing, Computer-Assisted/methods , Laser Coagulation , Placenta/surgery , Vascular Surgical Procedures/methods , Female , Humans , Pregnancy , Sensitivity and SpecificityABSTRACT
OBJECTIVE: The objective of the study was to test the hypothesis that inflammation modulates fetal erythroblastosis and/or the release of nucleated red blood cells (NRBCs) independent of hypoxia or fetal stress. We sought to determine whether fetal inflammation is associated with an elevation in neonatal NRBC count in the setting of inflammation-associated preterm birth. STUDY DESIGN: The relationships between peripheral NRBC count, histological chorioamnionitis, umbilical cord interleukin (IL)-6, erythropoietin (EPO), cortisol, and acid-base status were analyzed in 68 preterm singletons, born to mothers who had an amniocentesis to rule out infection. Proteomic profiling of amniotic fluid identified presence of intraamniotic inflammation according to established parameters. NRBC counts were assessed within 1 hour of birth. Early-onset neonatal sepsis (EONS) was established based on hematological and microbiological indices. IL-6, EPO, and cortisol levels were measured by immunoassays. Fetal acid-base status was determined within 10 minutes of delivery. Parametric or nonparametric statistics were used. RESULTS: Fetuses with EONS (n = 19) were delivered at earlier gestational ages (mean +/- SD: 27.1 +/- 2.8 weeks, P = .001) and more often by mothers with intraamniotic inflammation (P = .022) and histological chorioamnionitis (P < .001). Neonates with EONS had higher absolute NRBC counts (P = .011). NRBC counts were directly correlated with cord blood IL-6 levels (P < .001) but not with EPO, cortisol or parameters of acid-base status levels regardless of EONS status. These relationships remained following correction for gestational age, diabetes, intrauterine growth restriction, and steroid exposure. CONCLUSION: In the setting of inflammation-associated preterm birth and in the absence of hypoxia, elevations in NRBCs in the early neonatal period may be a direct response of exposure to inflammatory mediators in utero.
Subject(s)
Chorioamnionitis/immunology , Erythroblasts/metabolism , Fetal Distress/blood , Premature Birth/immunology , Sepsis/immunology , Adult , Chorioamnionitis/blood , Erythroblastosis, Fetal/blood , Erythroblastosis, Fetal/immunology , Erythrocyte Count , Female , Humans , Hypoxia/blood , Hypoxia/immunology , Infant, Newborn , Inflammation Mediators , Male , Pregnancy , Premature Birth/blood , Sepsis/bloodABSTRACT
OBJECTIVE: Receptor for advanced glycation end products (RAGE) is a multiligand cell-surface receptor part of the immunoglobulin superfamily with crucial roles in inflammation. S100A12/ENRAGE, a biomarker of amniotic fluid (AF) inflammation, is a ligand for RAGE. sRAGE, a competitive soluble RAGE receptor, inhibits RAGE ligands. Here we aimed to investigate the presence and changes in components of the RAGE system in women with intra-amniotic infection and inflammation. STUDY DESIGN: AF was retrieved by amniocentesis in 113 women stratified as follows: (1) positive AF culture (+AFC; GA = 27 [20-33] wk; n = 27); (2) negative AF culture (-AFC; GA = 30 [20-36] wk; n = 27); (3) second trimester control (2T-CRL; GA = 19 [15-25] wk; n = 31); (4) third trimester control (3T-CRL; GA = 36 [31-38] wk; n = 28). We used mass spectrometry (SELDI) to detect S100A12/ENRAGE in AF. sRAGE levels were measured using specific immunoassays. Placental pathology was interpreted in relationship to the presence or absence of histologic acute inflammation and immunoreactivity of S100A12/ENRAGE and RAGE. mRNA expression of S100A12/ENRAGE, sRAGE, and RAGE in amniochorion and placental villous tissue was investigated using quantitative real-time polymerase chain reaction (PCR). RESULTS: Presence of the S100A12/ENRAGE biomarker SELDI peak was confirmed in 70% of the +AFC but in only 10% of the -AFC samples (P < .001). The inflammatory biomarker was absent in all control samples. We further determined that the competitive inhibitor sRAGE is temporally regulated during gestation and that its AF levels are not influenced by the presence of either intra-amniotic infection or inflammation. Histologic choriamnionitis associated with intense staining for S100A12/ENRAGE, particularly in inflammatory cells. The immunoreactivity for extracellular domain of RAGE was localized exclusively to amnion epithelial, decidual, and extravillous trophoblast cells. Yet, acute histologic chorioamnionitis was related to increased gene expression of S100A12/ENRAGE in fetal membranes and decreased sRAGE and RAGE in the placenta. CONCLUSION: The S100A12/ENRAGE system is markedly upregulated in women with intra-amniotic infection and correlates with the degree of inflammation. Further studies remain to elucidate whether the gestational age dependence of the inhibitor molecule sRAGE may explain the higher incidence of infection-related preterm deliveries and especially rupture of the membranes at earlier gestational age.
Subject(s)
Amniotic Fluid/chemistry , Chorioamnionitis/immunology , Receptors, Immunologic/analysis , S100 Proteins/analysis , Adult , Biomarkers/analysis , Female , Humans , Neutrophils/immunology , Pregnancy , Receptor for Advanced Glycation End Products , Receptors, Immunologic/immunology , S100 Proteins/immunology , S100A12 Protein , Up-RegulationSubject(s)
Amnion/pathology , Fetofetal Transfusion/pathology , Placenta/pathology , Pregnancy Complications/surgery , Triplets , Amnion/surgery , Amniotic Band Syndrome/pathology , Female , Fetofetal Transfusion/etiology , Humans , Infant, Newborn , Laser Coagulation/adverse effects , Limb Deformities, Congenital/etiology , Placenta/surgery , Pregnancy , Pregnancy Complications/etiology , Young AdultABSTRACT
OBJECTIVE: An association between cesarean delivery and an increased risk of stillbirth in a subsequent pregnancy has been reported in the United Kingdom. This study investigated the association between prior cesarean delivery and unexplained intrauterine fetal demise at term in the United States. STUDY DESIGN: We conducted a cross-sectional study using the U.S. perinatal mortality data (1995 to 1997). Women aged 15 to 44 years with singleton term (37 weeks or longer) pregnancies were included in the analysis. Study groups were defined as pregnant women with a prior cesarean delivery (prior cesarean delivery) and women with no prior cesarean delivery (no cesarean delivery). Adjustments were made for maternal age, race, underlying medical conditions, and fetal congenital abnormalities. The Cochran-Mantel-Haenszel method was used for relative risk estimation at the 95% confidence interval calculation. RESULTS: A total of 11,061,599 deliveries of singleton pregnancies were recorded in the United States from January 1, 1995, to December 31, 1997. The cesarean delivery rate was 19.6%. The crude term intrauterine fetal demise rate was 1.5 per 1000 births for no cesarean delivery and 1.3 per 1000 births for prior cesarean delivery. After correction for parity greater than 1, congenital anomalies, and underlying maternal medical conditions, term intrauterine fetal demise rates were 0.6 and 0.4 per 1000 births for no cesarean delivery and prior cesarean delivery, respectively. Restriction of the analysis to women with only 1 prior delivery resulted in term intrauterine fetal demise rates of 0.8 and 0.7 per 1000 births for no cesarean delivery and prior cesarean delivery, respectively (relative risk 0.90; 95% confidence interval 0.76-1.06). CONCLUSION: A prior cesarean delivery is not associated with an increased risk of stillbirth in a subsequent pregnancy.
Subject(s)
Cesarean Section/adverse effects , Infant Mortality , Stillbirth , Adult , Cesarean Section/statistics & numerical data , Cross-Sectional Studies , Female , Humans , Infant, Newborn , Parity , Pregnancy , Risk Assessment , United States/epidemiologyABSTRACT
PROBLEM: Neutrophil gelatinase-associated lipocalin (NGAL) is expressed in neutrophils and involved in innate immunity by sequestering iron. NGAL's ability to complex with matrix metalloproteinase-9 (MMP-9) and extend its gelatinolytic activity led us to investigate its role in pregnancies complicated by preterm birth (PTB) and intra-amniotic infection/inflammation (IAI). METHOD OF STUDY: We assayed the amniotic fluid (AF) levels of NGAL and MMP-9 in 308 women that had a clinically indicated amniocentesis and a normal pregnancy outcome or PTB. qRT-PCR was employed to determine NGAL mRNA expression of placental villous trophoblast and amniochorion. Immunohistochemistry was used for cellular localization. RESULTS: AF NGAL levels were gestational age-regulated. Women with IAI and PTB had significantly higher levels of NGAL, MMP-9 and NGALâ¢MMP-9 complex. CONCLUSION: The amniochorion is a source of NGAL and similarly to other inflammatory conditions, this protein may augment the collagenolytic effect of MMP-9 and modulate host-microbe interactions in pregnancies complicated by IAI.
Subject(s)
Amniotic Fluid/metabolism , Bacterial Infections/metabolism , Lipocalin-2/biosynthesis , Matrix Metalloproteinase 9/biosynthesis , Pregnancy Complications, Infectious/metabolism , Premature Birth/metabolism , Adult , Amniotic Fluid/microbiology , Bacterial Infections/microbiology , Chorion/metabolism , Chorion/microbiology , Female , Gene Expression Regulation , Humans , Inflammation/metabolism , Inflammation/microbiology , Inflammation/pathology , Pregnancy , Pregnancy Complications, Infectious/microbiology , Premature Birth/pathology , Prospective Studies , Trophoblasts/metabolism , Trophoblasts/microbiologyABSTRACT
OBJECTIVE: To investigate the effect of structured didactic lectures by leaders in the field of Maternal-Fetal Medicine on reported clinical decision-making. METHODS: An interactive survey of obstetric management was performed as part of a postgraduate course at the 2004 Annual Meeting of the Society for Maternal-Fetal Medicine. Seven controversial topics were addressed, including tocolytic therapy, progesterone supplementation for the prevention of preterm birth, screening for inherited thrombophilia, cervical cerclage for a shortened cervix, the management of preterm premature rupture of membranes, magnesium sulfate seizure prophylaxis, and dexamethasone therapy for hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome. The survey was carried out before and after a series of structured didactic lectures, thereby allowing for analysis of the effect of the lectures on reported clinical decision-making. RESULTS: A total of 298 obstetric care providers attended the postgraduate course. By report, the majority of attendees were Maternal-Fetal Medicine specialists (60.7%), less than 10 years out from specialty training (56.3%), and practicing in a university-based setting (52.9%). An average of 233 practitioners (range 157-298) answered each question. Comparison of responses to the survey given before and after the lectures demonstrated significant differences, especially in the areas of tocolytic therapy and inherited thrombophilias. CONCLUSIONS: Postgraduate lectures by leaders in the field of Maternal-Fetal Medicine have significant immediate impact on reported clinical decision-making.
Subject(s)
Attitude of Health Personnel , Decision Making , Education, Continuing , Gynecology/education , Obstetrics/education , Anti-Inflammatory Agents/therapeutic use , Cerclage, Cervical , Dexamethasone/therapeutic use , Female , Fetal Membranes, Premature Rupture/prevention & control , Genetic Testing , HELLP Syndrome/drug therapy , Humans , Magnesium Sulfate/therapeutic use , Midwifery/education , Obstetric Nursing/education , Pregnancy , Premature Birth/prevention & control , Seizures/chemically induced , Seizures/prevention & control , Surveys and Questionnaires , Thrombophilia/diagnosis , Thrombophilia/genetics , Tocolytic Agents/therapeutic use , United StatesABSTRACT
The North American Fetal Therapy Network is a consortium of 30 medical institutions in the United States and Canada with established expertise in fetal therapy and other forms of multidisciplinary care for complex fetal disorders. This publication is the third in a series of articles written by NAFTNet about monochorionic pregnancies. In this article, we provide the general obstetric practitioner with information regarding management options available for complications of monochorionic gestations. This information may be useful for a better understanding of the pathophysiology of the various conditions, for better patient counseling, for timely referral to a regional treatment center, and for ongoing comanagement after treatment.
Subject(s)
Diseases in Twins/therapy , Fetal Therapies/standards , Practice Guidelines as Topic , Pregnancy Complications/therapy , Ultrasonography, Prenatal/methods , Computer Communication Networks/organization & administration , Consensus , Diseases in Twins/diagnostic imaging , Female , Fetal Growth Retardation , Fetal Therapies/trends , Gestational Age , Humans , North America , Pregnancy , Pregnancy Complications/diagnosis , Program Evaluation , Twinning, MonozygoticABSTRACT
PROBLEM: TLR4 mediates host responses to pathogens through a mechanism that involves protein myeloid differentiation-2 (MD-2) and its soluble form sMD-2. The role of sMD2 in intra-amniotic inflammation-induced preterm birth has not been previously explored. METHOD OF STUDY: Human amniotic fluid (AF) sMD-2 was studied by Western blotting in 152 AF samples of patients who had an amniocentesis to rule-out infection (yes infection, n = 50; no infection, n = 50) or women with normal pregnancy outcome (second trimester genetic karyotyping, n = 26; third trimester lung maturity testing, n = 26). Histological localization and mRNA expression of MD2 in fetal membranes were studied by immunohistochemistry and RT-PCR. The ability of fetal membrane to release sMD-2 and inflammatory cytokines was studied in vitro. RESULTS: Human AF contains three sMD-2 proteoforms whose levels of expression were lower at term. Intra-amniotic infection upregulated sMD-2. MD-2 mRNA and immunohistochemistry findings concurred. In vitro, LPS and monensin increased, while cycloheximide decreased sMD-2 production. Recombinant sMD-2 modulated TNF-α and IL-6 levels in a dose- and time-dependent fashion. CONCLUSION: sMD2 proteoforms are constitutively present in human AF. The intensity of the intra-amniotic inflammatory response to bacteria or perhaps to other TLR4 ligands may be facilitated through synthesis and release of sMD2 by the amniochorion.