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Objective: Placenta accreta is clinically associated with maternal uterine scar. Our objective was to investigate the biochemical contribution of maternal scarring to hyperinvasive trophoblast. We hypothesised that trophoblast over-invasion in placenta accreta is associated with aberrant invasion-site signalling of growth and angiogenic factors known to be involved in wound healing and promotion of cell invasion through the epithelial to mesenchymal cellular programme.Design: Cross-sectional series.Setting: Yale-New Haven Hospital.Population: Women with histologically confirmed normal and abnormal placentation.Methods: Placental invasion site tissue sections were immunostained for endoglin and other angiogenic regulators, and transforming growth factor β (TGFβ) proteins. Maternal serum endoglin, and the vascular endothelial growth factor (VEGF) mediators hypoxia-inducible factor-1α (HIF1α) and endostatin, were assessed using immunoassay.Main Outcome Measures: Differences in median H-score by immunostaining and in mean serum level by immunoassay.Results: By immunostaining, placenta accreta samples demonstrated intervillous endoglin shedding and increased trophoblast expression of its cleavage protein matrix metalloproteinase-14. Absent decidual HIF1α and endostatin were observed in areas of VEGF upregulation. TGFβ1 was present in myocytes but not in collagen bundles into which accreta trophoblast invaded. Maternal serum endoglin decreased in praevia and accreta when corrected for gestational age.Conclusion: Angiogenic and growth factors at the placental invasion site are altered in accreta, both by decidual absence and within myometrial scar. We postulate this promotes the invasive phenotype of placenta accreta by activating hyperinvasive trophoblast and by dysregulating placental vascular remodelling.Funding: Yale Department of Obstetrics, Gynecology and Reproductive Sciences funds.Tweetable Abstract: Placenta accreta histology shows dysregulation of angiogenic and growth factors. [ABSTRACT FROM AUTHOR]

Objectives: The objective of this study was to determine the effect of chronic nitric oxide synthase inhibition on heart rate and intravascular blood pressure in unrestrained pregnant rats as recorded by radiotelemetry.Study Design: Heart rate and systolic and diastolic blood pressures were monitored beginning with day 6 of pregnancy and until 1 week post partum with a radiotelemetric device. On day 10 of pregnancy osmotic minipumps were implanted subcutaneously and loaded to continuously deliver N(G)-nitro-L -arginine methyl ester (50 mg/d per rat, n = 6 animals) or vehicle (control group, n = 6 animals).Results: Blood pressure in the animals treated with N(G)-nitro-L -arginine methyl ester significantly increased compared with that in the control group and heart rate significantly decreased immediately after nitric oxide synthase blockade. Blood pressure then trended downward as gestation progressed, until the difference between the control group and the group treated with N(G)-nitro-L -arginine methyl ester became nonsignificant after day 17. Refractoriness to nitric oxide synthase blockade was especially evident in the diastolic pressure. Systolic, diastolic, and mean blood pressures in the rats treated with N(G)-nitro-L -arginine methyl ester were again significantly higher than those in the control group immediately after delivery and remained so despite a lower heart rate until the experiment was ended on postpartum day 6.Conclusions: Radiotelemetry can be used to monitor heart rate and intra-arterial blood pressure in unstressed, unrestrained animals. Chronic inhibition of nitric oxide does not cause sustained hypertension throughout pregnancy. Nitric oxide does not appear to be the only factor responsible for the vascular changes in pregnancy. The factors responsible for the refractoriness to nitric oxide synthase blockade are specific to pregnancy and disappear immediately after delivery. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this study was to analyze records of uterine electrical activity made from the abdominal surface of pregnant and laboring rats to examine whether similar quantitative information can be extracted as from direct recording from the uterine muscle.Study Design: Electrical activity during pregnancy (nonlabor, days 18 to 22), term labor (day 22), and preterm labor (onapristone injected on day 18, delivery on day 19) was measured with use of electrodes attached to the uterine wall and to the abdominal surface. The fast Fourier transform and wavelet transforms were obtained for representative electromyographic bursts. Power spectra were generated. Intrauterine pressure was also measured.Results: (1) Several parameters have been identified for use in following up the progressive increase in uterine activity that occurs in preparation for and during labor. Analyses of amplitude, frequency, and percent time active represent a convenient method for objectively determining the efficiency of uterine contraction. (2) Most of the changes in these parameters appear in the last 24 hours before delivery. (3) Although the uterine electromyographic signals on the abdominal surface are attenuated, the abdominal surface signals are generally similar to the signals obtained from the uterine muscle during pregnancy and during preterm and term labor. (4) The characteristics of onapristone-induced preterm labor are generally similar to those of spontaneous term labor.Conclusions: Recording of uterine electromyographic activity from the abdominal surface may be useful in following the progression of pregnancy and in predicting and diagnosing labor. [ABSTRACT FROM AUTHOR]

Objectives: Our goals were to present a modified Abbe-Mcindoe technique of vaginoplasty with split-thickness skin graft and to analyze 51 years of experience in performing this procedure.Study Design: Two hundred one women with vaginal agenesis were diagnosed and operated on by the same surgeon in 51 years (1943 through 1994). The patients' ages ranged from 14 to 41 years with an average of 20.5 years (SD 3.9 years). In most of the cases surgical intervention was performed when the patient desired to begin her sexual experience. The graft was taken from the thigh or gluteal region, followed by dissection of the urethrovesicorectal space. The access in this space was performed through two mutually perpendicular incisions (a modification of the Abbe-Mcindoe technique). A multiholed, rigid plastic mold was inserted during surgery and was replaced after 8 to 10 days with a semirigid silicone mold, which remained in place at least 6 months after operation or until the patient became sexually active.Results: We retrospectively reviewed 201 cases of Mayer-Rokitansky-Küster-Hauser syndrome in which vaginoplasty was performed. The data were obtained from the personal records of Dan Alessandrescu, MD, PhD, for the 76 cases operated on between 1943 and 1967 and from the medical records in the Polizu Hospital Archive, Bucharest, Romania, for 125 cases operated on between 1968 and 1994. Overall surgical mortality was null. Intraoperative and postoperative complications consisted of two rectal perforations (1%), eight graft infections (4.0%), and 11 infections of graft-site origin (5.5%). Additional information was obtained during follow-up. Sexual satisfaction was investigated with objective (depth of constructed vagina) and subjective (ability to have sexual intercourse, presence or absence of dyspareunia, vaginal lubrication, orgasm) criteria and was analyzed on a qualitative scale. In 12 patients we performed biopsies of the neovaginal wall for histologic evaluation.Conclusion: Because of the simplicity, low morbidity, and high success rate, our modified Abbe-Mcindoe technique is a procedure of choice for vaginoplasty. [ABSTRACT FROM AUTHOR]

Preterm labour and resultant preterm birth are the most important problems in perinatology. Countless efforts have failed to establish a single effective treatment of preterm labour, partly because the mechanisms regulating the uterus and cervix during pregnancy are not well understood. New knowledge is needed to inhibit early progression of labour (uterine contractility and cervical ripening), and adequate quantitative tools to evaluate the uterus and cervix during pregnancy are lacking. In this review, we outline studies showing that the uterus (myometrium) and cervix pass through a conditioning step in preparation for labour. This step is not easily identifiable with present methods to assess the uterus or cervix. In the uterus, this seemingly irreversible step consists of changes in the electrical properties to make muscle more excitable and responsive to produce forceful contractions. In the cervix, the step consists of softening of the connective tissue components. Progesterone appears to have a dominant role in controlling both the uterus and cervix, as antiprogestins induce early, preterm conditioning leading to preterm labour. Apparently, nitric oxide (NO) also controls conditioning of the uterus and cervix. In the uterus, NO, in concert with progesterone, inhibits uterine contractility. At term, NO production by the uterus and placenta are decreased and allow labour to progress. In contrast, NO in the cervix increases at the end of pregnancy and it may be the final pathway for stimulating cervical ripening by activation of metalloenzymes. The progress of labour can be assessed non-invasively using electromyographic (EMG) signals from the uterus (the driving force for contractility) recorded from the abdominal surface. Uterine EMG bursts detected in this manner characterize uterine contractile events during human and animal pregnancy. A low uterine EMG activity, measured transabdominally throughout most of pregnancy, rises dramatically during labour. EMG activity also increases substantially during preterm labour in humans and rats. This method may be used one day to predict impending preterm labour and identify control steps and treatments. A quantitative method also assesses the cervix, using an optical device which measures collagen fluorescence in the cervix. The collascope estimates cervical collagen content from a fluorescent signal generated when collagen cross-links are illuminated with excitation light of about 340 nm. The system has proved useful in rats and humans at various stages of pregnancy, and indicates that cervical softening occurs progressively in the last one-third of pregnancy. In rats, collascope readings correlate with resistance measurements made in the isolated cervix, which may help to assess cervical function during pregnancy, and indicate control and treatments. [ABSTRACT FROM AUTHOR]

Objective: The fetal consequences of intrapartum fetal tachycardia with maternal fever or clinical chorioamnionitis are not well studied. We evaluated the association between perinatal morbidity and fetal tachycardia in the setting of intrapartum fever., Study Design: Secondary analysis of a multicenter randomized control trial that enrolled 5,341 healthy laboring nulliparous women ≥36 weeks' gestation. Women with intrapartum fever ≥ 38.0°C (including those meeting criteria for clinical chorioamnionitis) after randomization were included in this analysis. Isolated fetal tachycardia was defined as fetal heart rate (FHR) ≥160 beats per minute for at least 10 minutes in the absence of other FHR abnormalities. FHR abnormalities other than tachycardia were excluded from the analysis. The primary outcome was a perinatal composite (5-minute Apgar's score ≤3, intubation, chest compressions, or mortality). Secondary outcomes included low arterial cord pH (pH < 7.20), base deficit ≥12, and cesarean delivery., Results: A total of 986 (18.5%) of women in the trial developed intrapartum fever, and 728 (13.7%) met criteria to be analyzed; of these, 728 women 336 (46.2%) had maternal-fetal medicine (MFM) reviewer-defined fetal tachycardia, and 349 of the 550 (63.5%) women during the final hour of labor had validated software (PeriCALM) defined fetal tachycardia. After adjusting for confounders, isolated fetal tachycardia was not associated with a significant difference in the composite perinatal outcome (adjusted odds ratio [aOR] = 3.15 [0.82-12.03]) compared with absence of tachycardia. Fetal tachycardia was associated with higher odds of arterial cord pH <7.2, aOR = 1.48 (1.01-2.17) and of infants with a base deficit ≥ 12, aOR = 2.42 (1.02-5.77), but no significant difference in the odds of cesarean delivery, aOR = 1.33 (0.97-1.82)., Conclusion: Fetal tachycardia in the setting of intrapartum fever or chorioamnionitis is associated with significantly increased fetal acidemia defined as a pH <7.2 and base excess ≥12 but not with a composite perinatal morbidity., Key Points: · The perinatal outcomes associated with fetal tachycardia in the setting of maternal fever are undefined.. · Fetal tachycardia was not significantly associated with perinatal morbidity although the sample size was limited.. · Fetal tachycardia was associated with an arterial cord pH <7.2 and base deficit of 12 or greater.., Competing Interests: None declared., (Thieme. All rights reserved.)

Background: Intention-to-treat analyses do not address adherence. Per protocol analyses treat nonadherence as a protocol deviation and assess if the intervention is effective if followed., Objective: To determine the rate of early preterm birth (EPTB, <34 weeks gestation) and preterm birth (PTB, <37 weeks gestation) in participants who adhered to a randomly assigned docosahexaenoic acid (DHA) dose of 1000 mg/day., Study Design: Eleven hundred women with a singleton pregnancy were enrolled before 20-weeks' gestation, provided a capsule with 200 mg/day DHA and randomly assigned to two additional capsules containing a placebo or 800 mg of DHA. In the Bayesian Adaptive Design, new randomization schedules were determined at prespecified intervals. In each randomization, the group with the most EPTB was assigned fewer participants than the other group. Adherence was defined a priori as a postpartum red blood cell phospholipid DHA (RBC-PL-DHA) ≥5.5%.and post hoc as ≥8.0% RBC-PL-DHA, the latter after examination of postpartum RBC-PL-DHA. Bayesian mixture models were fitted for gestational age and dichotomized for EPTB and PTB as a function of baseline RBC-PL-DHA and dose-adherence. Bayesian hierarchical models were also fitted for EPTB by dose adherence and quartiles of baseline RBC-PL-DHA., Results: Adherence to the high dose using both RBC-PL-DHA cut points resulted in less EPTB compared to 200 mg [Bayesian posterior probability (pp) = 0.93 and 0.92, respectively]. For participants in the two lowest quartiles of baseline DHA status, adherence to the higher dose resulted in lower EPTB (≥5.5% RBC-PL-DHA, quartiles 1 and 2, pp = 0.95 and 0.96; ≥8% RBC-PL-DHA, quartiles 1 and 2, pp = 0.94 and 0.95). Using the Bayesian model, EPTB was reduced by 65%, from 3.45% to 1.2%, using both cut points. Adherence also reduced PTB before 35, 36 and 37 weeks using both cut points (pp ≥ 0.95). In general, performance of the nonadherent subgroup mirrored that of participants assigned to 200 mg., Conclusion: Adherence to high dose DHA reduced EPTB and PTB. The largest effect of adherence on reducing EPTB was observed in women with low baseline DHA levels., Clinicaltrials: gov (NCT02626299)., Competing Interests: Conflict of interest SEC has received honorariums for presentations about DHA in infancy and pregnancy. SEC, BJG and CJV were PIs of R01HD083292, CJV was an employee of RB Nutrition, which produces infant formulas and supplements with DHA at the time the study was conducted, however, RB was not involved in the study execution or analysis. She conducted this study through her role as an Adjunct Professor at The University of Cincinnati. The other authors have no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Numerous pediatric neurogenetic diseases may be optimally treated by in utero gene therapy (IUGT); but advancing such treatments requires animal models that recapitulate developmental physiology relevant to humans. One disease that could benefit from IUGT is the autosomal recessive motor neuron disease spinal muscular atrophy (SMA). Current SMA gene-targeting therapeutics are more efficacious when delivered shortly after birth, however postnatal treatment is rarely curative in severely affected patients. IUGT may provide benefit for SMA patients. In previous studies, we developed a large animal porcine model of SMA using AAV9 to deliver a short hairpin RNA (shRNA) directed at porcine survival motor neuron gene (Smn) mRNA on postnatal day 5. Here, we aimed to model developmental features of SMA in fetal piglets and to demonstrate the feasibility of prenatal gene therapy by delivering AAV9-shSmn in utero. Saline (sham), AAV9-GFP, or AAV9-shSmn was injected under direct ultrasound guidance between gestational ages 77-110 days. We developed an ultrasound-guided technique to deliver virus under direct visualization to mimic the clinic setting. Saline injection was tolerated and resulted in viable, healthy piglets. Litter rejection occurred within seven days of AAV9 injection for all other rounds. Our real-world experience of in utero viral delivery followed by AAV9-related fetal rejection suggests that the domestic sow may not be a viable model system for preclinical in utero AAV9 gene therapy studies., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Maternal-fetal consequences of exposure to blue-wavelength light are poorly understood. This study tested the hypothesis that evening blue-light exposure is associated with maternal fasting glucose and infant birthweight. Forty-one pregnant women (body mass index = 32.90 ± 6.35 kg/m 2 ; 24-39 years old; 16 with gestational diabetes mellitus [GDM]) wore actigraphs for 7 days, underwent polysomnography, and completed study questionnaires during gestational week 30 ± 3.76. Infant birthweight (n = 41) and maternal fasting glucose (n = 30; range = 16-36 weeks) were recorded from the mothers' medical charts. Blue-light exposure was obtained from Actiwatch-Spectrum recordings. Adjusted and unadjusted linear regression analyses were performed to determine sleep characteristics associated with maternal fasting glucose and infant-birthweight. The mean fasting mid- to late-gestation glucose was 95.73 ± 24.68 mg/dl and infant birthweight was 3271 ± 436 g. In unadjusted analysis, maternal fasting glucose was associated with blue-light exposure (β = 3.82, p = 0.03). In the final model of multiple linear regression for fasting glucose, evening blue-light exposure (β = 4.00, p = 0.01) remained significant after controlling for gestational weight gain, parity, sleep duration, and GDM. Similarly, blue-light exposure was associated with infant birthweight (69.79, p = 0.006) in the unadjusted model, and remained significant (β = 70.38, p = 0.01) after adjusting for weight gain, wakefulness after sleep onset, gestational age at delivery, and GDM. Higher blue-light exposure in pregnancy is associated with higher fasting glucose and infant birthweight. Reduced use of electronic devices before bedtime is a modifiable behavior., (© 2022 The Authors. Annals of the New York Academy of Sciences published by Wiley Periodicals LLC on behalf of New York Academy of Sciences.)

Depression and posttraumatic stress disorder increase the risk of idiopathic preterm birth (iPTB); however, the exact molecular mechanism is unknown. Depression and stress-related disorders are linked to increased FK506-binding protein 51 (FKBP51) expression levels in the brain and/or FKBP5 gene polymorphisms. Fkbp5 -deficient ( Fkbp5 -/- ) mice resist stress-induced depressive and anxiety-like behaviors. FKBP51 binding to progesterone (P4) receptors (PRs) inhibits PR function. Moreover, reduced PR activity and/or expression stimulates human labor. We report enhanced in situ FKBP51 expression and increased nuclear FKBP51-PR binding in decidual cells of women with iPTB versus gestational age-matched controls. In Fkbp5 +/+ mice, maternal restraint stress did not accelerate systemic P4 withdrawal but increased Fkbp5 , decreased PR, and elevated AKR1C18 expression in uteri at E17.25 followed by reduced P4 levels and increased oxytocin receptor ( Oxtr ) expression at 18.25 in uteri resulting in PTB. These changes correlate with inhibition of uterine PR function by maternal stress-induced FKBP51. In contrast, Fkbp5 -/- mice exhibit prolonged gestation and are completely resistant to maternal stress-induced PTB and labor-inducing uterine changes detected in stressed Fkbp5 +/+ mice. Collectively, these results uncover a functional P4 withdrawal mechanism mediated by maternal stress-induced enhanced uterine FKBP51 expression and FKPB51-PR binding, resulting in iPTB., Competing Interests: The authors declare no competing interest., (Copyright © 2021 the Author(s). Published by PNAS.)

Objective: This study aimed to determine if intrapartum placement of an intrauterine pressure catheter (IUPC) is associated with an increased rate of surgical site infections in women undergoing a cesarean delivery., Study Design: This was a secondary analysis of the prospective observational Maternal-Fetal Medicine Units Network Vaginal Birth after Cesarean Registry. We compared patients with and without IUPC use. A multivariable logistic regression was performed to evaluate for an association between IUPC use and postcesarean surgical site infections., Results: The study included 16,887 women: 7,441 with IUPC use and 9,446 without IUPC use. After adjustment for potential cofounders, IUPC use was associated with an increased risk of postcesarean infections compared with those without IUPC use (adjusted odds ratio: 1.28; 95% confidence interval: 1.10-1.50; p  = 0.002)., Conclusion: IUPC use is associated with an increased risk of postcesarean surgical site infections. This supports the judicious use of IUPC for limited clinical indications and provides a potential area of focus for reduction in postcesarean infections., Competing Interests: None declared., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Objective: To evaluate sex-specific genetic susceptibility to adverse neurodevelopmental outcome (ANO, defined as cerebral palsy [CP], mental, or psychomotor delay) at risk for early preterm birth (EPTB, < 32 weeks)., Study Design: Secondary case-control analysis of a trial of magnesium sulfate (MgSO 4 ) before anticipated EPTB for CP prevention. Cases are infants who died by the age of 1 year or developed ANO. Controls, matched by maternal race and infant sex, were neurodevelopmentally normal survivors. Neonatal DNA was evaluated for 80 polymorphisms in inflammation, coagulation, vasoregulation, excitotoxicity, and oxidative stress pathways using Taqman assays. The primary outcome for this analysis was sex-specific ANO susceptibility. Conditional logistic regression estimated each polymorphism's odds ratio (OR) by sex stratum, adjusting for gestational age, maternal education, and MgSO 4 -corticosteroid exposures. Holm-Bonferroni corrections, adjusting for multiple comparisons ( p  < 7.3 × 10 -4 ), accounted for linkage disequilibrium between markers., Results: Analysis included 211 cases (134 males; 77 females) and 213 controls (130 males; 83 females). An interleukin-6 (IL6) polymorphism (rs2069840) was associated with ANO in females (OR: 2.6, 95% confidence interval [CI]: 1.5-4.7; p  = 0.001), but not in males (OR: 0.8, 95% CI: 0.5-1.2; p  = 0.33). The sex-specific effect difference was significant ( p  = 7.0 × 10 -4 ) and was unaffected by MgSO 4 exposure. No other gene-sex associations were significant., Conclusion: An IL6 gene locus may confer susceptibility to ANO in females, but not males, after EPTB., Competing Interests: None declared., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Objective: Reliable semiquantitative assessment of histological placental acute inflammation is problematic, even among experts. Tissue samples in histology slides often show variability in the extent and location of neutrophil infiltrates. We sought to determine whether the variability in pathologists' scoring of neutrophil infiltrates in the placenta could be reduced by the use of 'regions of interest' (ROIs) that break the sample into smaller components., Design: ROIs were identified within stained H&E slides from a cohort of 56 women. ROIs were scored using a semiquantitative scale (0-4) for the average number of neutrophils by at least two independent raters., Setting: Preterm singleton births at Yale New Haven Hospital., Participants: This study used stained H&E placental slides from a cohort of 56 women with singleton pregnancies who had a clinically indicated amniocentesis within 24 hours of delivery., Primary and Secondary Outcome Measures: Interrater agreement was assessed with the intraclass correlation coefficient (ICC) and log-linear regression. Predictive validity was assessed using amniotic fluid protein profile scores (neutrophil defensin-2, neutrophil defensin-1, calgranulin C and calgranulin A)., Results: Excellent agreement by the ICC was found for the average neutrophil scores within a region of interest. Log-linear analyses suggest that even where there is disagreement, responses are positively associated along the diagonal. There was also strong evidence of predictive validity comparing pathologists' scores with amniotic fluid protein profile scores., Conclusions: Agreement among observers of semiquantitative neutrophil scoring through the use of digitised ROIs was demonstrated to be feasible with high reliability and validity., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Objective An acquired uterine arteriovenous malformation (AVM) is a rare cause of vaginal bleeding and, although hysterectomy is the definitive therapy, transcatheter embolization (TCE) provides an alternative treatment option. This systematic review presents the indications, technique, and outcomes for transcatheter treatment of the acquired uterine AVMs. Study Design Literature databases were searched from 2003 to 2013 for eligible clinical studies, including the patient characteristics, procedural indication, results, complications, as well as descriptions on laterality and embolic agents utilized. Results A total of 40 studies were included comprising of 54 patients (average age of 33.4 years). TCE had a primary success rate with symptomatic control of 61% (31 patients) and secondary success rate of 91% after repeated embolization. When combined with medical therapy, symptom resolution was noted in 48 (85%) patients without more invasive surgical procedures. Conclusion Low-level evidence supports the role of TCE, including in the event of persistent bleeding following initial embolization, for the treatment of acquired uterine AVMs. The variety of embolic agents and laterality of approach delineate the importance of refining procedural protocols in the treatment of the acquired uterine AVM. Condensation A review on the management of patients with acquired uterine AVMs.

Introduction: Epithelial-to-mesenchymal transition (EMT) is a process of molecular and phenotypic epithelial cell alteration promoting invasiveness. Loss of E-cadherin (E-CAD), a transmembrane protein involved in cell adhesion, is a marker of EMT. Proteolysis into N- and C-terminus fragments by ADAM10 and presenilin-1 (PSEN-1) generates soluble (sE-CAD) and transcriptionally active forms. We studied the protein expression patterns of E-CAD in the serum and placenta of women with histologically-confirmed over-invasive placentation., Methods: The patterns of expression and levels of sE-CAD were analyzed by Western blot, immunoassay, and immunoprecipitation. Tissue immunostaining for E-CAD, cytokeratin-7 (epithelial marker), vimentin (mesenchymal marker), ADAM10, PSEN-1 and β-catenin expression were investigated in parallel., Results: N-terminus cleaved 80 kDa sE-CAD fragments were present in serum of pregnant women with gestational age regulation of the circulatory levels. Women with advanced trophoblast invasion did not display circulatory levels of sE-CAD different from those of women with normal placentation. Histologically, extravillous trophoblasts (EVT) closer to the placental-myometrial interface demonstrated less E-CAD staining than those found deeper in the myometrium. These cells expressed both vimentin and cytokeratin, an additional feature of EMT. EVT of placentas with advanced invasion displayed intracellular E-CAD C-terminus immunoreactivity predominating over that of the extracellular N-terminus, a pattern consistent with preferential PSEN-1 processing., Discussion: Local processing of E-CAD may be an important molecular mechanism controlling the invasive phenotype of accreta EVT., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: The most common congenital heart disease in the newborn population, patent ductus arteriosus, accounts for significant morbidity in preterm newborns. In addition to prematurity and environmental factors, we hypothesized that genetic factors play a significant role in this condition., Objective: The objective of this study was to quantify the contribution of genetic factors to the variance in liability for patent ductus arteriosus in premature newborns., Patients and Methods: A retrospective study (1991-2006) from 2 centers was performed by using zygosity data from premature twins born at < or =36 weeks' gestational age and surviving beyond 36 weeks' postmenstrual age. Patent ductus arteriosus was diagnosed by echocardiography at each center. Mixed-effects logistic regression was used to assess the effect of specific covariates. Latent variable probit modeling was then performed to estimate the heritability of patent ductus arteriosus, and mixed-effects probit modeling was used to quantify the genetic component., Results: We obtained data from 333 dizygotic twin pairs and 99 monozygotic twin pairs from 2 centers (Yale University and University of Connecticut). Data on chorioamnionitis, antenatal steroids, gestational age, body weight, gender, respiratory distress syndrome, patent ductus arteriosus, necrotizing enterocolitis, oxygen supplementation, and bronchopulmonary dysplasia were comparable between monozygotic and dizygotic twins. We found that gestational age, respiratory distress syndrome, and institution were significant covariates for patent ductus arteriosus. After controlling for specific covariates, genetic factors or the shared environment accounted for 76.1% of the variance in liability for patent ductus arteriosus., Conclusions: Preterm patent ductus arteriosus is highly familial (contributed to by genetic and environmental factors), with the effect being mainly environmental, after controlling for known confounders.

Background: Cardiovascular development is vital for embryonic survival and growth. Early gestation embryo loss or malformation has been linked to yolk sac vasculopathy and congenital heart defects (CHDs). However, the molecular pathways that underlie these structural defects in humans remain largely unknown hindering the development of molecular-based diagnostic tools and novel therapies., Methodology/principal Findings: Murine embryos were exposed to high glucose, a condition known to induce cardiovascular defects in both animal models and humans. We further employed a mass spectrometry-based proteomics approach to identify proteins differentially expressed in embryos with defects from those with normal cardiovascular development. The proteins detected by mass spectrometry (WNT16, ST14, Pcsk1, Jumonji, Morca2a, TRPC5, and others) were validated by Western blotting and immunoflorescent staining of the yolk sac and heart. The proteins within the proteomic dataset clustered to adhesion/migration, differentiation, transport, and insulin signaling pathways. A functional role for several proteins (WNT16, ADAM15 and NOGO-A/B) was demonstrated in an ex vivo model of heart development. Additionally, a successful application of a cluster of protein biomarkers (WNT16, ST14 and Pcsk1) as a prenatal screen for CHDs was confirmed in a study of human amniotic fluid (AF) samples from women carrying normal fetuses and those with CHDs., Conclusions/significance: The novel finding that WNT16, ST14 and Pcsk1 protein levels increase in fetuses with CHDs suggests that these proteins may play a role in the etiology of human CHDs. The information gained through this bed-side to bench translational approach contributes to a more complete understanding of the protein pathways dysregulated during cardiovascular development and provides novel avenues for diagnostic and therapeutic interventions, beneficial to fetuses at risk for CHDs.

Objective: To determine the relationship between presence of amniotic fluid (AF) biomarkers characteristic of inflammation (defensins 2 and 1 and calgranulins C and A) and fetal inflammatory status at birth., Design: Prospective observational cohort., Setting: Tertiary referral University hospital., Population: One hundred and thirty-two consecutive mothers (gestational age, median [interquartile range]: 29.6 [24.1-33.1] weeks) who had a clinically indicated amniocentesis to rule out infection and their newborns., Methods: Intra-amniotic inflammation was diagnosed by mass spectrometry surface-enhanced-laser-desorption-ionization time of flight (SELDI-TOF). The AF proteomic fingerprint (mass-restricted [MR] score) ranges from 0-4 (none to all biomarkers present). The intensity of intra-amniotic inflammation was graded based on the number of proteomic biomarkers: MR score 0: 'no' inflammation, MR score 1-2: 'minimal' inflammation and MR score 3-4: 'severe' inflammation. At birth, cord blood was obtained for all women. Severity of histological chorioamnionitis and early-onset neonatal sepsis (EONS) was based on established histological and haematological criteria. Interleukin-6 (IL-6) levels were measured by sensitive immunoassays. The cord blood-to-AF IL-6 ratio was used as an indicator of the differential inflammatory response in the fetal versus the AF compartment., Main Outcome Measures: To relate proteomic biomarkers of intra-amniotic infection to cord blood IL-6 and to use the latter as the primary marker of fetal inflammatory response., Results: Women with intra-amniotic inflammation delivered at an earlier gestational age (analysis of variance, P<0.001) and had higher AF IL-6 levels (P<0.001). At birth, neonates of women with severe intra-amniotic inflammation had higher cord blood IL-6 levels (P=0.002) and a higher frequency of EONS (P=0.002). EONS was characterised by significantly elevated cord blood IL-6 levels (P<0.001). Of the 39 neonates delivered by mothers with minimal intra-amniotic inflammation, 15 (39%) neonates had umbilical cord blood IL-6 levels above the mean for the group and 2 neonates had confirmed sepsis. The severity of the neutrophilic infiltrate in the chorionic plate (P<0.001), choriodecidua (P=0.002), umbilical cord (P<0.001) but not in the amnion (P>0.05) was an independent predictor of the cord blood-to-AF IL-6 ratio. Relationships were maintained following correction for gestational age, birthweight, amniocentesis-to-delivery interval, caesarean delivery, status of the membranes, race, MR score and antibiotics and steroid exposure., Conclusions: We provide evidence that presence of proteomic biomarkers characteristic of inflammation in the AF is associated with an increased inflammatory status of the fetus at birth. Neonates mount an increased inflammatory status and have positive blood cultures even in the context of minimal intra-amniotic inflammation.