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The coronavirus SARS-CoV-2 is cause of a global pandemic of a pneumonia-like disease termed Coronavirus Disease 2019 (COVID-19). COVID-19 presents a high mortality rate, estimated at 3.4%. More than 1 out of 4 hospitalized COVID-19 patients require admission to an Intensive Care Unit (ICU) for respiratory support, and a large proportion of these ICU-COVID-19 patients, between 17% and 46%, have died. In these patients COVID-19 infection causes an inflammatory response in the lungs that can progress to inflammation with cytokine storm, Acute Lung Injury (ALI), Acute Respiratory Distress Syndrome (ARDS), thromboembolic events, disseminated intravascular coagulation, organ failure, and death. Mesenchymal Stem Cells (MSCs) are potent immunomodulatory cells that recognize sites of injury, limit effector T cell reactions, and positively modulate regulatory cell populations. MSCs also stimulate local tissue regeneration via paracrine effects inducing angiogenic, anti-fibrotic and remodeling responses. MSCs can be derived in large number from the Umbilical Cord (UC). UC-MSCs, utilized in the allogeneic setting, have demonstrated safety and efficacy in clinical trials for a number of disease conditions including inflammatory and immune-based diseases. UC-MSCs have been shown to inhibit inflammation and fibrosis in the lungs and have been utilized to treat patients with severe COVID-19 in pilot, uncontrolled clinical trials, that reported promising results. UC-MSCs processed at our facility have been authorized by the FDA for clinical trials in patients with an Alzheimer’s Disease, and in patients with Type 1 Diabetes (T1D). We hypothesize that UC-MSC will also exert beneficial therapeutic effects in COVID-19 patients with cytokine storm and ARDS. We propose an early phase controlled, randomized clinical trial in COVID-19 patients with ALI/ARDS. Subjects in the treatment group will be treated with two doses of UC-MSC (100 x 106 cells). The first dose will be infused within 24 hours following study enrollment. A second dose will be administered 72 ± 6 hours after the first infusion. Subject in the control group will receive infusion of vehicle (DPBS supplemented with 1% HSA and 70 U/kg unfractionated Heparin, delivered IV) following the same timeline. Subjects will be evaluated daily during the first 6 days, then at 14, 28, 60, and 90 days following enrollment (see Schedule of Assessment for time window details). Safety will be determined by adverse events (AEs) and serious adverse events (SAEs) during the follow-up period. Efficacy will be defined by clinical outcomes, as well as a variety of pulmonary, biochemical and immunological tests. Success of the current study will provide a framework for larger controlled, randomized clinical trials and a means of accelerating a possible solution for this urgent but unmet medical need. The proposed early phase clinical trial will be performed at the University of Miami (UM), in the facilities of the Diabetes Research Institute (DRI), UHealth Intensive Care Unit (ICU) and the Clinical Translational Research Site (CTRS) at the University of Miami Miller School of Medicine and at the Jackson Memorial Hospital (JMH).

Vein of Galen malformations (VOGMs) are rare and complex congenital vascular anomalies that can lead to severe morbidity and mortality. Management predominantly focuses on postnatal endovascular interventions. However, these may not be feasible for fetuses with hemodynamic instability and high-output cardiac failure and may fail to prevent irreversible brain damage induced by prolonged compression by the venous varix, hemodynamic alterations and resultant potential ischemic injury. In utero endovascular embolization in high-risk VOGM fetuses may decrease mortality, prevent cardiac decompensation, and improve neurological and cognitive outcomes, thereby potentially establishing a novel standard of care for these challenging cases. We present a case of a fetus with VOGM, managed via a multidisciplinary approach through ultrasound-guided, in utero endovascular embolization. The procedure was successfully performed without complications, and the mother was discharged in good condition. At birth and a 3-month follow-up, the newborn demonstrated normal heart and respiratory function. The newborn is scheduled for diagnostic angiography and potential embolization at 6 months post-delivery., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: To evaluate whether hypertensive disorders of pregnancy, including gestational hypertension, preeclampsia, and eclampsia, are associated with cognitive decline later in life among U.S. Hispanic/Latina individuals., Methods: The HCHS/SOL (Hispanic Community Health Study/Study of Latinos) is a prospective population-based study of Hispanic/Latino individuals aged 18-74 years from four U.S. communities. This analysis included parous individuals aged 45 years or older who participated in the HCHS/SOL clinic study visit 1 (2008-2011) neurocognitive assessment and subsequently completed a repeat neurocognitive assessment as part of the Study of Latinos-Investigation of Neurocognitive Aging ancillary study visit 2 (2015-2018). Hypertensive disorders of pregnancy were assessed retrospectively by self-report of any gestational hypertension, preeclampsia, or eclampsia. Cognitive functioning was measured at both study visits with the Brief Spanish-English Verbal Learning Test, Digit Symbol Substitution, and Word Fluency. A regression-based approach was used to define cognitive decline at visit 2 as a function of cognition at visit 1 after adjustment for age, education, and follow-up time. Linear regression models were used to determine whether hypertensive disorders of pregnancy or their component diagnoses were associated with standardized cognitive decline after adjustment for sociodemographic characteristics, clinical and behavioral risk factors, and follow-up time., Results: Among 3,554 individuals included in analysis, the mean age was 56.2 years, and 467 of individuals (13.4%) reported at least one hypertensive disorder of pregnancy. Individuals with hypertensive disorders of pregnancy compared with those without were more likely to have higher mean systolic blood pressure, fasting glucose, and body mass index. After an average of 7 years of follow-up, in fully adjusted models, gestational hypertension was associated with a 0.17-SD relative decline in Digit Symbol Substitution scores (95% CI, -0.31 to -0.04) but not other cognitive domains (Brief Spanish-English Verbal Learning Test or Word Fluency). Neither preeclampsia nor eclampsia was associated with neurocognitive differences., Conclusion: The presence of preeclampsia or eclampsia was not associated with interval neurocognitive decline. In this cohort of U.S. Hispanic/Latina individuals, gestational hypertension alone was associated with decreased processing speed and executive functioning later in life., Competing Interests: Financial Disclosure Tali Elfassy received support from the NIH/National Institute on Minority Health and Health Disparities (MD014158). Shathiyah Kulandavelu received support from American Heart Association (19CDA34660102). Leah Dodds received support from the NIH/National Heart, Lung, and Blood Institute (HL165894). Krista M. Perreira's institution received payment from the NIH, Russell Sage Foundation, and the Urban Institute. She received an honorarium from the University of Tennessee. Richard B. Lipton received payment from AbbVie, Amgen, and Pfizer. Dr. Lipton is the Edwin S. Lowe Professor of Neurology at the Albert Einstein College of Medicine in New York. He receives research support from the NIH: 2PO1 AG003949 (mPI), 1RF1 AG057531 (site PI), RF1 AG054548 (investigator), 1RO1 AG048642 (investigator), R56 AG057548 (investigator), RO1 AG060933 (investigator), RO1 AG062622 (investigator), 1UG3FD006795 (mPI), 1U24NS113847 (investigator), U01 AT011005 (investigator), 1R01 AG075758 (pending, investigator), 1R01 AG077639 (pending, investigator), and K23 NS107643 (mentor). He also receives support from the Migraine Research Foundation and the National Headache Foundation and research grants from TEVA, Satsuma, and Amgen. He serves on the Editorial Board of Neurology , is a senior advisor to Headache , and is an associate editor for Cephalalgia . He has reviewed for the National Institute on Aging and National Institute of Neurological Disorders and Stroke; holds stock and stock options in Biohaven Holdings as well as stock options in Manistee; and serves as consultant or advisory board member for or has received honoraria from the following: AbbVie (Allergan), American Academy of Neurology, American Headache Society, Amgen, Avanir, Axon, Axsome, Biohaven, Biovision, Boston Scientific, Dr. Reddy's (Promius), Electrocore, Eli Lilly, eNeura Therapeutics, Equinox, GlaxoSmithKline, Grifols, Lundbeck (Alder), Merck, Pernix, Pfizer, Satsuma, Supernus, Teva, Trigemina, Vector, and Vedanta. He receives royalties from Wolff's Headache 7th and 8th editions, Oxford Press University, 2009, Wiley and Informa. The other authors did not report any potential conflicts of interest., (Copyright © 2024 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Problem: Although endometrial receptivity is a key factor in influencing implantation in both naturally conceived and assisted reproductive technology (ART) cycles, very little is known about the endometrium milieu around the time of implantation. Previous studies have demonstrated the presence of several cytokines in the endometrium that affect implantation. However, there is lacking data about the presence of immune cell subtypes within the endometrium and in the uterine cavity at the time of implantation., Method of Study: This study was approved by the Institutional Review Board (# 225589). The study was designed as a prospective observational cohort study between May 2021 and December 2022 at a single academic-based fertility center. All patients underwent at least one In Vitro Fertilization (IVF) cycle and have frozen embryos. Twenty-four participants were recruited for this study which was conducted during the frozen embryo transfer (FET) cycle regardless of the outcome of previous cycles. Two samples were acquired from each subject, denoted as lower and upper. A trial transfer catheter was introduced under ultrasound guidance into the lower uterine segment. Upon removal, the tip was rinsed in IMDM medium containing 10% FBS (lower uterus). A transfer catheter was then loaded with the embryo that was placed in the upper uterus under ultrasound guidance. The tip of the transfer catheter was rinsed in separate aliquot of the above media (upper uterus). After centrifugation, pelleted cells were stained for the following surface markers: CD45, CD3, CD19, CD4, CD8, gamma delta TCR, CD25, CD127, CD66b, CD14, CD16, CD56 and acquired on Sony SP6800 Spectral Analyzer., Results: Upon staining the pelleted cells, we were able to identify viable leukocytes from samples obtained from both, upper and lower uterus (0.125 × 10 6 cells ± SD 0.32), (0.123 × 10 6 cells ± SD 0.12), respectively. Among total viable cells, there was no significant difference in both percent and number of CD45+ cells between the upper and lower uterus (9.88% ± 6.98 SD, 13.67% ± 9.79 SD, p = .198) respectively. However, there was significantly higher expression of CD3+ (p = .006), CD19+ (p = .032) and CD14+ (p = .019) cells in samples collected from upper compared to lower uterus. Within all CD3+ cells, we found that gamma delta T cells (GDT) were the major population of T cells in both upper and lower uterus. In contrast, CD8+ T cells were significantly higher in the lower uterus when compared to the upper uterus (p = .009). There was no statistically significant difference in the expression of CD4+ T cells, T regulatory cells (CD4+CD25+CD127-), NK cells (CD56+), neutrophils (CD66b+) and FcγRIII+ cells (CD16+) between upper and lower uterus., Conclusions: We believe the immune milieu at the time of embryo transfer will affect implantation. Understanding the composition of immune cells will guide further research in identifying optimal immune milieus that favor implantation. Comprehensive analysis of endometrium is expected to lead to new diagnostic and therapeutic approaches to improve IVF outcomes., (© 2024 The Authors. American Journal of Reproductive Immunology published by John Wiley & Sons Ltd.)

With an estimated 100,000 new cases yearly worldwide, Guillain-Barre syndrome (GBS) is the most common cause of flaccid paralysis. GBS is exceedingly rare in pregnancy and carries high maternal and fetal risk. We report a case of a 38-year-old essential primigravida who presented at 38 weeks six days gestational age with ascending paraplegia progressing to dysarthria, dysphagia, and facial weakness. A clinical diagnosis of GBS was made in an outside institution, supported by elevated protein on lumbar puncture. During the antepartum period, a diagnosis of gestational hypertension progressed to preeclampsia with severe features when a sudden rise in liver function tests occurred. The patient underwent an uneventful planned cesarean delivery but could not be extubated due to respiratory failure. After a 20-day critical care admission, she was extubated and had an improvement in neurologic status to near her baseline., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Swonger et al.)

We present a case of disseminated Pneumocystis jirovecii pneumonia in a patient with a medical history of glioblastoma multiforme associated with acute deep-vein thrombosis. The patient presented to the emergency department with clinical features of pulmonary infection, and the chest images showed pneumonia. Antibiotics were initiated (azithromycin, cefepime, and vancomycin) and the patient was transferred to the ward for further management, where the condition of the patient continued to worsen over the second day. The patient developed bilateral lower extremity swelling and the doppler ultrasound revealed bilateral lower extremity acute deep vein thrombosis. Laboratory results showed pancytopenia and transaminitis. However, a repeated chest X-ray showed ground-glass changes and interstitial infiltrates, suggestive of atypical infection. We indeed identified D-glucan which hints to a disseminated form of Pneumocystis jirovecii pneumonia infection in this patient. We further confirmed the Pneumocystis jirovecii pneumonia by polymerase chain reaction test from the fluid obtained via bronchoalveolar lavage. We, therefore, initiated intravenous trimethoprim/ sulfamethoxazole treatment with an anticoagulant, and the patient's condition improved. Our findings strongly suggest a possible link between Pneumocystis jirovecii pneumonia infection and thrombogenesis, with impact in medical practice., Competing Interests: Conflict of interests: The authors declare no conflicts of interest., (Copyright © 2022, Hussain H. et al., Applied Systems and Discoveries Journals.)

Failed or altered gliogenesis is a major characteristic of diffuse white matter injury in survivors of premature birth. The developmentally regulated long noncoding RNA (lncRNA) H19 inhibits S-adenosylhomocysteine hydrolase (SAHH) and contributes to methylation of diverse cellular components, such as DNA, RNA, proteins, lipids, and neurotransmitters. We showed that the pregnancy-derived synthetic PreImplantation Factor (sPIF) induces expression of the nuclear receptor corepressor 2 (NCOR2) via H19/SAHH-mediated DNA demethylation. In turn, NCOR2 affects oligodendrocyte differentiation markers. Accordingly, after hypoxic-ischemic brain injury in rodents, myelin protection and oligodendrocytes' fate are in part modulated by sPIF and H19. Our results revealed an unexpected mechanism of the H19/SAHH axis underlying myelin preservation during brain recovery and its use in treating neurodegenerative diseases can be envisioned.

Problem: It is unknown whether maternal cytokine production differs between twin and singleton gestations in the implantation phase. A difference in maternal serum cytokine concentrations in twins would imply a dose-response to the invading embryos, as opposed to a general immune reaction., Method of Study: A prospective longitudinal cohort of women aged 18-45 at an academic fertility center undergoing in vitro fertilization and embryo transfer (IVF-ET) underwent routine collection of serial serum samples starting 9 days after ET and then approximately every 48 hours thereafter. Cryopreserved aliquots of these samples were assayed for interleukin-10 (IL-10), tumor necrosis factor-alpha (TNF-α), and C-X-C motif chemokine ligand 10 (CXCL10) using the SimplePlex immunoassay platform. Pregnancies were followed until delivery. Serial measures of serum concentrations of IL-10, CXCL10, and TNF-α in singleton or di-di twin pregnancies from 9 to 15 days after IVF-ET were compared., Results: Maternal serum levels of CXCL10 are significantly lower in women with di-di twin pregnancies in early implantation compared to those with singleton gestation (day 9-11, P = .02). Serum levels of TNF-α and IL-10 were comparable at all studied time points (P > .05)., Conclusion: Maternal serum levels of CXCL10 are significantly lower in the earliest implantation phase in di-di twins compared to singleton conceptions. Given the known anti-angiogenic role of CXCL10, we hypothesize that lower CXCL10 levels in twin implantations allow an environment that is conducive for the greater vascularization required for the establishment of dual placentation in di-di twins., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Understanding what happens at the time of embryo implantation has been the subject of significant research. Investigators from many differing fields including maternal fetal medicine, microbiology, genetics, reproductive endocrinology and immunology have all been studying the moment the embryo interacts with the maternal endometrium. A perfect relationship between the uterus and the embryo, mediated by a tightly controlled interaction between the embryo and the endometrium, is required for successful implantation. Any factors affecting this communication, such as altered microbiome may lead to poor reproductive outcomes. Current theories suggest that altered microbiota may trigger an inflammatory response in the endometrium that affects the success of embryo implantation, as inflammatory mediators are tightly regulated during the adhesion of the blastocyst to the epithelial endometrial wall. In this review, we will highlight the various microbiome found during the periconceptual period, the microbiomes interaction with immunological responses surrounding the time of implantation, its effect on implantation, placentation and ultimately maternal and neonatal outcomes., (Copyright © 2020 Bardos, Fiorentino, Longman and Paidas.)

Problem: Embryo implantation and placentation require a careful immunological balance. Cytokines such as IL-10 and TNFα have been implicated as markers of dysregulation, but have only been studied at a single time point or after a pregnancy loss. Our objective was to determine normative patterns of serum levels of IL-10 and TNFα and their ratio throughout the first trimester in healthy pregnancies and to determine if this pattern differs from pregnancy loss., Method of Study: Two prospective longitudinal cohorts of gravidae including in vitro fertilization (IVF) and naturally conceived pregnancies with serial blood draws. Cytokines were assayed using Simple Plex. In the IVF cohort, we monitored from the implantation day up to 6 weeks of gestation; whereas in the naturally conceived cohort, sample collection began at 4 weeks and throughout the whole first trimester., Results: IL-10 concentrations in normal pregnancies were significantly higher than in pregnancies ending in a loss starting at 6-8 weeks of gestation, while TNFα concentrations were significantly lower in normal than in pregnancies ending in a loss starting at 3-5 of gestation weeks. The IL-10 to TNFα ratio in normal pregnancies was significantly higher from 4 to 9 weeks compared to pregnancies that were lost (t test, P < .05). Changes were observed before any symptoms of miscarriage were present., Conclusion: We provide evidences of differences in early immunomodulation in healthy pregnancies vs those destined to end in first-trimester loss. The ratio of IL-10 to TNFα rises significantly higher in viable pregnancies as early as 4.5 weeks compared to pregnancies loss., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Metformin is the most widely used anti-diabetic medication worldwide. However, human and animal studies suggest that prenatal metformin exposure may increase the risk of metabolic disorders in adult offspring, yet the underpinning mechanism remains unclear. Here we report that metformin-exposed mouse fetuses exhibit elevated expression of the H19 long noncoding RNA, which induces hypomethylation and increased expression of hepatocyte nuclear factor 4α (HNF4α). As a transcription factor essential for morphological and functional differentiation of hepatocytes, HNF4α also has an indispensable role in the regulation of expression of gluconeogenic genes. Consistently, H19 overexpression in a human liver cell line leads to decreased methylation and increased expression of Hnf4α, with concomitant activation of the gluconeogenic program. Mechanistically, we show that the methylation change of Hnf4α is induced by H19-mediated regulation of S-adenosylhomocysteine hydrolase. We also provide evidence that altered H19 expression is a direct effect of metformin in the fetal liver. Our results suggest that metformin from the mother can directly act upon the fetal liver to modify Hnf4α expression, a key factor for both liver development and function, and that perturbation of this H19/Hnf4α-mediated pathway may contribute to the fetal origin of adult metabolic abnormalities.

Antithrombin (AT) deficiency is a high-risk thrombophilia and a rare condition. Despite full anticoagulation during pregnancy and the postpartum period, women with AT deficiency may still be vulnerable to developing venous thromboembolism (VTE), including fatal events. There is limited guidance on the management of AT deficiency in pregnancy, including the role of AT concentrates. Following a comprehensive review of the state of the art with respect to recommendations and guidelines, our expert panel in maternal-fetal medicine, hematology and basic science reached consensus on key issues in the recognition and management of AT deficiency in pregnancy. This paper summarizes the state of the art and summarizes what we believe are best practices with special emphasis on a multidisciplinary approach involving obstetrics and hematology in the care of women with AT deficiency., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The development of a mammalian brain is a complex and long-lasting process. Not surprisingly, preterm birth is the leading cause of death in newborns and children. Advances in perinatal care reduced mortality, but morbidity still represents a major burden. New therapeutic approaches are thus desperately needed. Given that mesenchymal stem/stromal cells (MSCs) emerged as a promising candidate for cell therapy, we transplanted MSCs derived from the Wharton's Jelly (WJ-MSCs) to reduce the burden of immature brain injury in a murine animal model. WJ-MSCs transplantation resulted in protective activity characterized by reduced myelin loss and astroglial activation. WJ-MSCs improved locomotor behavior as well. To address the underlying mechanisms, we tested the key regulators of responses to DNA-damaging agents, such as cyclic AMP-dependent protein kinase/calcium-dependent protein kinase (PKA/PKC), cyclin-dependent kinase (CDK), ataxia-telangiectasia-mutated/ATM- and Rad3-related (ATM/ATR) substrates, protein kinase B (Akt), and 14-3-3 binding protein partners. We characterized WJ-MSCs using a specific profiler polymerase chain reaction array. We provide evidence that WJ-MSCs target pivotal regulators of the cell fate such as CDK/14-3-3/Akt signaling. We identified leukemia inhibitory factor as a potential candidate of WJ-MSCs' induced modifications as well. We hypothesize that WJ-MSCs may exert adaptive responses depending on the type of injury they are facing, making them prominent candidates for cell therapy in perinatal injuries.

Acute Radiation Syndrome (ARS) may lead to cancer and death and has few effective countermeasures. Efficacy of synthetic PIF treatment was demonstrated in preclinical autoimmune and transplantation models. PIF protected against inflammation and mortality following lethal irradiation in allogeneic bone marrow transplant (BMT) model. Herein, we demonstrate that PIF imparts comprehensive local and systemic protection against lethal and sub-lethal ARS in murine models. PIF treatment 2 h after lethal irradiation led to 100% survival and global hematopoietic recovery at 2 weeks after therapy. At 24 h after irradiation PIF restored hematopoiesis in a semi-allogeneic BMT model. PIF-preconditioning provided improved long-term engraftment. The direct effect of PIF on bone marrow cells was also demonstrated in vitro: PIF promoted pre-B cell differentiation and increased immunoregulatory properties of BM-derived mesenchymal stromal cells. PIF treatment also improved hematopoietic recovery and reduced systemic inflammatory cytokine production after sub-lethal radiation exposure. Here, PIF also prevented colonic crypt and basal membrane damage coupled with reduced nitric oxide synthetase (iNOS) and increased (B7h1) expression. Global upper GI gene pathway analysis revealed PIF's involvement in protein-RNA interactions, mitochondrial oxidative pathways, and responses to cellular stress. Some effects may be attributed to PIF's influence on macrophage differentiation and function. PIF demonstrated a regulatory effect on irradiated macrophages and on classically activated M1 macrophages, reducing inflammatory gene expression (iNOS, Cox2), promoting protective (Arg1) gene expression and inducing pro-tolerance cytokine secretion. Notably, synthetic PIF is stable for long-term field use. Overall, clinical investigation of PIF for comprehensive ARS protection is warranted.

Fetal growth restriction (FGR) is a well-recognized risk factor for perinatal mortality and morbidity, as well as neurodevelopmental impairment and adulthood onset disorders. Here we report that the H19 long noncoding RNA (lncRNA) is significantly decreased in placentae from pregnancies with FGR. Downregulation of H19 leads to reduced migration and invasion of extravillous trophoblast (EVT) cells in vitro. This is consistent with reduced trophoblast invasion that has been observed in FGR. Genome-scale transcriptome profiling of EVT cells reveals significantly decreased expression of the type III TGF-β receptor (TβR3) following H19 knockdown. Decreased TβR3 expression is also seen in FGR placentae. TβR3 repression decreases EVT cell migration and invasion, owing to impaired TGF-β signaling through a non-canonical TGF-β signaling pathway. Further, we identify TβR3 as a novel regulatory target of microRNA let-7. We propose that dysregulation of this newly identified H19/TβR3-mediated regulatory pathway may contribute to the molecular mechanism of FGR. Our findings are the first to show a lncRNA-based mechanism of FGR, holding promise for the development of novel predictive, diagnostic, and therapeutic modalities for FGR., Competing Interests: All authors declare no conflicts of interest related to this work.

Objective: Preeclampsia is one of the top six causes of maternal mortality in the United States (US) and is associated with considerable perinatal morbidity and mortality. Evidence suggests the US incidence of preeclampsia has increased dramatically over the past two decades. This study aims to compile, summarize, and critique the literature on the health and economic burden of preeclampsia and early-onset preeclampsia., Study Design: We reviewed the literature for estimates of burden of preeclampsia and early-onset preeclampsia to both mother and child, summarized the evidence on economic and social burden, and highlighted current gaps in the literature., Results: No recent studies comprehensively assess the costs and health consequences of preeclampsia or early-onset preeclampsia for both mother and child. Where it exists, the literature suggests preeclampsia and early-onset preeclampsia cause numerous adverse health consequences, but these conditions currently lack effective treatment. The need for preterm delivery from early-onset preeclampsia suggests its costs are substantial: very (28-31 weeks) and extremely (<28 weeks) preterm birth cost approximately 40 and 100 times a term pregnancy, respectively., Conclusion: Given the severity of outcomes from preeclampsia, further research on its health and economic consequences is essential to inform policy and resource allocation decisions in health care., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

A synthetic peptide (sPIF) analogous to the mammalian embryo-derived PreImplantation Factor (PIF) enables neuroprotection in rodent models of experimental autoimmune encephalomyelitis and perinatal brain injury. The protective effects have been attributed, in part, to sPIF's ability to inhibit the biogenesis of microRNA let-7, which is released from injured cells during central nervous system (CNS) damage and induces neuronal death. Here, we uncover another novel mechanism of sPIF-mediated neuroprotection. Using a clinically relevant rat newborn brain injury model, we demonstrate that sPIF, when subcutaneously administrated, is able to reduce cell death, reverse neuronal loss and restore proper cortical architecture. We show, both in vivo and in vitro, that sPIF activates cyclic AMP dependent protein kinase (PKA) and calcium-dependent protein kinase (PKC) signaling, leading to increased phosphorylation of major neuroprotective substrates GAP-43, BAD and CREB. Phosphorylated CREB in turn facilitates expression of Gap43, Bdnf and Bcl2 known to have important roles in regulating neuronal growth, survival and remodeling. As is the case in sPIF-mediated let-7 repression, we provide evidence that sPIF-mediated PKA/PKC activation is dependent on TLR4 expression. Thus, we propose that sPIF imparts neuroprotection via multiple mechanisms at multiple levels downstream of TLR4. Given the recent FDA fast-track approval of sPIF for clinical trials, its potential clinical application for treating other CNS diseases can be envisioned.

Dysfunction and loss of neurons are the major characteristics of CNS disorders that include stroke, multiple sclerosis, and Alzheimer's disease. Activation of the Toll-like receptor 7 by extracellular microRNA let-7, a highly expressed microRNA in the CNS, induces neuronal cell death. Let-7 released from injured neurons and immune cells acts on neighboring cells, exacerbating CNS damage. Here we show that a synthetic peptide analogous to the mammalian PreImplantation factor (PIF) secreted by developing embryos and which is present in the maternal circulation during pregnancy inhibits the biogenesis of let-7 in both neuronal and immune cells of the mouse. The synthetic peptide, sPIF, destabilizes KH-type splicing regulatory protein (KSRP), a key microRNA-processing protein, in a Toll-like receptor 4 (TLR4)-dependent manner, leading to decreased production of let-7. Furthermore, s.c. administration of sPIF into neonatal rats following hypoxic-ischemic brain injury robustly rescued cortical volume and number of neurons and decreased the detrimental glial response, as is consistent with diminished levels of KSRP and let-7 in sPIF-treated brains. Our results reveal a previously unexpected mechanism of action of PIF and underscore the potential clinical utility of sPIF in treating hypoxic-ischemic brain damage. The newly identified PIF/TLR4/KSRP/let-7 regulatory axis also may operate during embryo implantation and development.

Reductions in uteroplacental flow initiate a cascade of molecular effects leading to hypoxia, thrombosis, inflammation, and endothelial cell dysfunction resulting in untoward pregnancy outcomes. In this review, we detail these effects and their relationship to preeclampsia (PE) and intrauterine growth restriction (IUGR).

Klippel-Trenaunay Syndrome (KTS) is a rare, sporadic triad of congenital malformations involving an extensive port wine stain, soft tissue or bone hypertrophy and underlying venous and/or lymphatic malformation involving an extremity. Pregnancy is known to exacerbate KTS complications and can put women at increased obstetrical risk due to deep venous thrombosis and other thromboembolic events. Here we report a case of a patient with KTS who achieved a pregnancy through in vitro fertilization (IVF) using her own eggs and a gestational surrogate in the setting of hypercoagulability and chronic consumptive coagulopathy.

Pulmonary embolism (PE) is the leading cause of maternal mortality in the developed world. Mortality from PE in pregnancy might be related to challenges in targeting the right population for prevention, ensuring that diagnosis is suspected and adequately investigated, and initiating timely and best possible treatment of this disease. Pregnancy is an example of Virchow's triad: hypercoagulability, venous stasis, and vascular damage; together these factors lead to an increased incidence of venous thromboembolism. This disorder is often suspected in pregnant women because some of the physiological changes of pregnancy mimic its signs and symptoms. Despite concerns for fetal teratogenicity and oncogenicity associated with diagnostic testing, and potential adverse effects of pharmacological treatment, an accurate diagnosis of PE and a timely therapeutic intervention are crucial. Appropriate prophylaxis should be weighed against the risk of complications and offered according to risk stratification., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Vascular injury increases access and binding of plasma-derived factor VII to perivascular cell membrane-bound tissue factor (TF). The resulting TF/VIIa complex promotes hemostasis by cleaving pro-thrombin to thrombin leading to the fibrin clot. In human pregnancy, decidual cell-expressed TF prevents decidual hemorrhage (abruption). During placentation, trophoblasts remodel decidual spiral arteries into high conductance vessels. Shallow trophoblast invasion impedes decidual vascular conversion, producing an inadequate uteroplacental blood flow that elicits abruption-related placental ischemia. Thrombin induces several biological effects via cell surface protease activated receptors. In first trimester human DCs thrombin increases synthesis of sFlt-1, which elicits placental ischemia by impeding angiogenesis-related decidual vascular remodeling. During pregnacy, the fibrillar collagen-rich amnion and choriodecidua extracellular matrix (ECM) provides greater than additive tensile strength and structural integrity. Thrombin acts as an autocrine/paracrine mediator that degrades these ECMs by augmenting decidual cell expression of: 1) matrix metalloproteinases and 2) interleukin-8, a key mediator of abruption-associated decidual infiltration of neutrophils, which express several ECM degrading proteases. Among the cell types at the maternal fetal interface at term, TF expression is highest in decidual cells indicating that this TF meets the hemostatic demands of labor and delivery. TF expression in cultured term decidual cells is enhanced by progestin and thrombin suggesting that the maintenance of elevated circulating progesterone provides hemostatic protection and that abruption-generated thrombin acts in an autocrine/paracrine fashion on decidual cells to promote hemostasis via enhanced TF expression.

Elevated serum transaminase levels can have many different etiologies, especially in the pregnant patient. Hypoxic hepatitis is a distinct syndrome caused by decreased hepatic blood flow that presents with a marked, but transient, increase in liver enzymes. A 28-year-old woman, gravida 3, para 2 with history of gastric bypass, presented in the second trimester with bright red blood per rectum, syncope, and epigastric pain. Laboratory studies were significant for anemia, elevated liver enzymes, and low platelets, raising concern for hemolysis, elevated liver enzymes, and low platelets (HELLP syndrome) and the need for emergent delivery. Complete evaluation included an upper endoscopy, which revealed a bleeding jejunal ulcer that was subsequently cauterized. Shortly after cauterization, the patient's laboratory values normalized and her pain resolved. Diagnosis of hypoxic hepatitis was made after exclusion of other liver-toxic entities, thus preventing delivery of a preterm infant. Hypoxic hepatitis may masquerade as other clinical syndromes, especially in the pregnant patient. Meticulous physical examination and assessment of laboratory values is essential for making a proper diagnosis and guiding management.

Inherited thrombophilias are not yet established as a cause of placenta-mediated pregnancy complications, such as fetal growth restriction, preeclampsia, abruption, and pregnancy loss. An inherited thrombophilia is only one of many factors that lead to development of these diseases and is unlikely to be the unique factor that should drive management in subsequent pregnancies. The paucity of evidence for benefit, coupled with a small potential for harm, suggests that low molecular weight heparin should be considered an experimental drug for these indications until data from controlled trials are published. At present, women with a history of placenta-mediated pregnancy complications, with or without a thrombophilia, should be followed closely without routine prophylactic low molecular weight heparin other than for prevention of venous thromboembolism in limited circumstances.

Objective: To estimate the relationship between histologic chorioamnionitis and four amniotic fluid proteomic biomarkers characteristic of inflammation (defensins 2 and 1, calgranulins C and A)., Methods: One hundred fifty-eight women with singleton pregnancies had a clinically indicated amniocentesis to rule out inflammation and infection in the context of preterm labor or preterm premature rupture of membranes. A proteomic fingerprint (Mass Restricted score) was generated from amniotic fluid using surface-enhanced laser desorption ionization time-of-flight mass spectrometry. The Mass Restricted score ranges from 0 to 4 (none to all four biomarkers present) in direct relationship with severity of intra-amniotic inflammation. Presence or absence of biomarkers was analyzed in relationship to placental pathology. Criteria for severity of histologic chorioamnionitis were 3 stages and 4 grades of inflammation of the amnion, choriodecidua and chorionic plate., Results: The prevalence of histologic chorioamnionitis was 64% (stage I 12%, stage II 16%, and stage III 37%). The Mass Restricted score significantly correlated with stages of histologic chorioamnionitis (r=0.539, P<.001), grades of choriodeciduitis (r=0.465, P<.001), and amnionitis (r=0.536, P<.001). African-American women were overrepresented in the group with severe inflammation (Mass Restricted score 3-4, P=.022). Of the four biomarkers of the Mass Restricted score, calgranulin C had the strongest relationship with presence of stage III chorioamnionitis, independent of race, amniocentesis-to-delivery interval, and gestational age., Conclusion: Proteomic analysis of amniotic fluid provides an opportunity for early recognition of histologic chorioamnionitis. This methodology may in the future identify candidates for antenatal therapeutic interventions., Level of Evidence: II.

There has been an sudden increase of knowledge about thrombophilias in the last decade as new thrombophilias are discovered and new associations are explored. It is now evident that thrombophilias are common and that the clinical consequences of having a thrombophilia do not appear to be limited to venous thromboembolism. The placenta-mediated pregnancy complications are also common (more than one in six pregnancies are affected) and include pregnancy loss, preeclampsia, placental abruption, and intrauterine growth restriction. These complications as a whole are the leading causes of maternal and neonatal morbidity in the developed world. Evidence has emerged to suggest that thrombophilic women may be at higher risk of developing these placenta-mediated pregnancy complications. However, is this evidence mature enough to claim that a causal association is proven? Is the evidence strong enough to recommend anticoagulant prophylaxis? We suggest that causality is not yet proven and that the data to support management with anticoagulant prophylaxis in thrombophilic pregnancies is too immature to consider this an established intervention.

Background: Successful trophoblast invasion and transformation of the maternal spiral arteries requires that the pregnant endometrium (i.e., decidua) act in an immunologically paradoxical fashion, accepting the semi-allogenic placenta, while maintaining host defenses against an array of microbial pathogens. In contrast to the growing evidence that the immune surveillance molecules known as Toll-like receptors (TLRs) are expressed by trophoblasts and fetal membranes, to date, no studies have been conducted on the decidua., Methods: Decidual tissues and cells were obtained from women undergoing first trimester elective terminations or repeat Cesarean sections and analyzed at both the protein and mRNA level., Results: We now demonstrate for the first time that human decidua differentially express TLRs and their downstream signaling molecules as well as TLR stimulated induction of cytokine production in the first and third trimester of pregnancy., Conclusions: These findings suggest that the decidua is a critical component of the innate immune response in pregnancy. Moreover, the results have implications for the success or failure of compromised pregnancies in early or late gestation.

Background: Proteomic analysis of amniotic fluid shows the presence of biomarkers characteristic of intrauterine inflammation. We sought to validate prospectively the clinical utility of one such proteomic profile, the Mass Restricted (MR) score., Methods and Findings: We enrolled 169 consecutive women with singleton pregnancies admitted with preterm labor or preterm premature rupture of membranes. All women had a clinically indicated amniocentesis to rule out intra-amniotic infection. A proteomic fingerprint (MR score) was generated from fresh samples of amniotic fluid using surface-enhanced laser desorption ionization (SELDI) mass spectrometry. Presence or absence of the biomarkers of the MR score was interpreted in relationship to the amniocentesis-to-delivery interval, placental inflammation, and early-onset neonatal sepsis for all neonates admitted to the Newborn Special Care Unit (n = 104). Women with "severe" amniotic fluid inflammation (MR score of 3 or 4) had shorter amniocentesis-to-delivery intervals than women with "no" (MR score of 0) inflammation or even "minimal" (MR score of 1 or 2) inflammation (median [range] MR 3-4: 0.4 d [0.0-49.6 d] versus MR 1-2: 3.8 d [0.0-151.2 d] versus MR 0: 17.0 d [0.1-94.3 d], p < 0.001). Nonetheless, a "minimal" degree of inflammation was also associated with preterm birth regardless of membrane status. There was a significant association between the MR score and severity of histological chorioamnionitis (r = 0.599, p < 0.001). Furthermore, neonatal hematological indices and early-onset sepsis significantly correlated with the MR score even after adjusting for gestational age at birth (OR for MR 3-4: 3.3 [95% CI, 1.1 to 9.2], p = 0.03). When compared with other laboratory tests routinely used to diagnose amniotic fluid inflammation and infection, the MR score had the highest accuracy to detect inflammation (white blood cell count > 100 cells/mm3), whereas the combination of Gram stain and MR score was best for rapid prediction of intra-amniotic infection (positive amniotic fluid culture)., Conclusions: High MR scores are associated with preterm delivery, histological chorioamnionitis, and early-onset neonatal sepsis. In this study, proteomic analysis of amniotic fluid was shown to be the most accurate test for diagnosis of intra-amniotic inflammation, whereas addition of the MR score to the Gram stain provides the best combination of tests to rapidly predict infection.

Recent evidence has linked preterm premature rupture of the fetal membranes (PPROM) to placental abruption. Because neutrophils are a rich source of proteases that can degrade extracellular matrix in abruption-associated PPROM, we examined whether decidual neutrophil infiltration complicates abruption-associated PPROM. Accordingly, immunostaining for the neutrophil marker CD15 was performed in placentas obtained after overt abruption (decidual hemorrhage) with or without PPROM and in control placentas. Abruptions were associated with a marked decidual neutrophil infiltration that peaked after PPROM, whereas decidua from gestational age-matched controls were virtually devoid of neutrophils. Neutrophil infiltrates co-localized with fibrin deposition. Because abruptions elicit intense decidua-enhanced thrombin production, we examined the regulation of abruption-induced neutrophil infiltration. Expression of the primary neutrophil chemoattractant interleukin-8 (IL-8) was evaluated in leukocyte-free term decidual cells incubated with estradiol (E2; control) or with E2+medroxyprogesterone acetate (to mimic pregnancy)+/-thrombin. After 24 hours, enzyme-linked immunosorbent assay measurements indicated that thrombin (0.1 to 2.5 U/ml) elicited a dose-dependent elevation in secreted IL-8 (P<0.05) with 2.5 U/ml of thrombin increasing IL-8 levels by >14-fold in E2 and E2+medroxyprogesterone incubations. Results were validated by Western blot and quantitative reverse transcriptase-polymerase chain reaction. In summary, thrombin-enhanced IL-8 expression in term decidual cells may explain how abruption-associated PPROM promotes decidual neutrophil infiltration.

Context: Decidual neutrophil infiltration complicates spontaneous abortions associated with inflammation and hemorrhage. Transendothelial neutrophil migration into inflamed tissues involves IL-8-mediated chemoattraction, then neutrophil attachment to endothelial cell-expressed intercellular adhesion molecule-1 (ICAM-1)., Objective: The aim of this study was to assess IL-8 and ICAM-1 regulation in decidual inflammation and hemorrhage; the effects of the proinflammatory cytokines, TNFalpha, IL-1beta and the hemostatic, proinflammatory cytokine thrombin were measured on IL-8 expression in first trimester decidual cells (DCs), and ICAM-1 immunostaining was compared in normal, inflamed, and hemorrhagic first trimester decidua., Design: Immunohistochemistry of human decidua and in vitro treatment of human decidual cells were performed., Setting: The study was conducted at the Academic Medical Center., Intervention: . DCs were passaged until they were leukocyte-free (CD45 free by FACS), then were incubated with estradiol or medroxyprogesterone acetate alone or with TNFalpha or IL-1beta or thrombin. Normal, inflamed, and hemorrhagic decidua were immunostained for ICAM-1 and the neutrophil marker CD14., Main Outcome Measure: ICAM-1 immunostaining was performed in decidua. IL-8 levels in DC-conditioned media were assessed by ELISA and immunoblotting; IL-8 mRNA levels were measured by quantitative RT-PCR., Results: Endothelial cell ICAM-1 immunostaining was similar in normal and inflamed or hemorrhagic decidua. In cultured DCs, optimal concentrations of IL-1beta, TNFalpha, and thrombin elevated secreted IL-8 levels by 1083 +/- 261-, 370 +/- 77-, and 45 +/- 15-fold, respectively (mean +/- SEM; P < 0.05; n = 8). The effects were dose dependent and were unaffected by medroxyprogesterone acetate. Western blotting confirmed the ELISA results, and corresponding effects on IL-8 mRNA levels were observed., Conclusions: Cytokine/thrombin-enhanced DC IL-8 expression interacts with constitutively expressed ICAM-1 in decidual endothelium to modulate neutrophil trafficking into hemorrhagic and inflamed first trimester decidua.

BACKGROUND: Echogenic intracardiac focus (EIF) has been identified as a common ultrasound finding in association with fetal aneuploidy. Little is known about the association of this soft marker aneuploidy in various ethnic groups. Although it is commonly thought Asians in general have a higher incidence of EIF, it is unknown whether this also applies to Japanese as a subpopulation. The purpose of this study is to determine the antenatal incidence and postnatal significance of EIF observed during sonography in Japanese patients. METHODS: A cohort of Japanese patients who underwent ultrasound screening from 1997 to 1999 in the ultrasound unit at the New York University School of Medicine was identified. Variables included age, gestational age, serum markers, and the presence or absence of aneuploidy. Patients with first degree paternal or maternal Japanese ancestry were included for analysis. Examinations were performed between 14 and 24 weeks gestation. The prevalence of EIF was calculated. The control group was based on previously published data in the U.S (7.3% prevalence). RESULTS: A total of 154 subjects were identified, 148 were available for final analysis. Twenty-two fetuses had an EIF, 19 (86.4%) left-sided, 3 (13.6%) right-sided. Seventeen patients had other sonographic markers associated with aneuploidy. The mean maternal age at diagnosis was 30.7 +/- 3.9 years and the mean gestational age was 19.8 +/- 1.6 weeks. The prevalence of EIF was 14.8%. Compared to published population prevalence, there was a statistically significant difference (p < 0.005). No abnormal karyotypes were found. CONCLUSION: Asians of Japanese origin may have a higher prevalence of echogenic intracardiac foci, thus affecting the positive predictive value of this sonographic marker for aneuploidy.

Objective: To describe the sonographic findings of sirenomelia during the first trimester on both two-dimensional sonography with color Doppler imaging and three-dimensional sonography., Methods: Two cases of sirenomelia in primiparous patients with histories of infertility are described. The diagnosis was made on the basis of two-dimensional sonography, and three-dimensional sonography was used to further characterize the findings., Results: Both fetuses had size-date discrepancies, increased nuchal translucency, large intra-abdominal vessels, and 2-vessel umbilical cords. Both pregnancies were terminated by dilation and curettage after the patients viewed the three-dimensional pictures of the fetuses., Conclusions: During the first trimester of pregnancy, rare and lethal anomalies can be diagnosed with a high degree of confidence if a thorough, age-dependent anatomic survey of the fetus is performed.

Objective: To determine whether fetal splenic enlargement predicts anemia in Rh-alloimmunized nonhydropic singleton fetuses., Methods: Splenic circumference was measured before funipuncture in 21 singleton pregnancies on 47 occasions. The spleen was imaged in an axial section of the fetal abdomen close to the level used for measurement of the abdominal circumference. The splenic length and width were measured and the circumference calculated by the formula (length and width x 1.57). One measurement per patient was used for each analysis. Splenic circumference was measured and expressed as multiples of the normal median (MoM) for gestational age. One hundred twenty-one cases were used to provide cross-sectional normative data. The expected median splenic circumference values were derived from a normal group. Fetal anemia was defined as hemoglobin deficit, ie, mean hemoglobin concentration for gestation minus the measured value. Anemia was defined as hemoglobin deficit exceeding 2 g/dL, and severe anemia as hemoglobin deficit exceeding 5 g/dL. Receiver operator characteristics curves for the prediction of anemia using different splenic circumference (MoM) values were constructed., Results: Splenic circumference was an excellent predictor of severe anemia in cases with no prior transfusion: sensitivity 100% and specificity 94.7% (area under the curve = .97, P < .03). The measurement did not correlate significantly with severe anemia in the group with prior transfusion (area under the curve = .73, P = .19)., Conclusion: Splenomegaly is sensitive for the detection of severe anemia in nonhydropic Rh sensitized cases without prior transfusion. The splenic enlargement could be explained by extramedullary erythropoiesis.

The increased use of prenatal sonography has led to earlier and more frequent diagnosis of a wide range of gastrointestinal anomalies. Many of these anomalies are associated with other severe cardiac, renal, and genetic abnormalities that may impact on decisions regarding timing and site of delivery. The majority of these patients should be referred to a center that provides perinatal, neonatal, and pediatric surgical expertise. After a complete prenatal evaluation, a decision regarding the site of delivery and the need for subspecialty referral can be made. Prenatal diagnosis of the conditions discussed in this article does not influence the mode of delivery, but subsequent management of the newborn is improved by delivery in a tertiary care center.