Clinical Opinion: The diagnosis and management of suspected fetal growth restriction: an evidence-based approach.

This study reviewed the literature about the diagnosis, antepartum surveillance, and time of delivery of fetuses suspected to be small for gestational age or growth restricted. Several guidelines have been issued by major professional organizations, including the International Society of Ultrasound in Obstetrics and Gynecology and the Society for Maternal-Fetal Medicine. The differences in recommendations, in particular about Doppler velocimetry of the ductus venosus and middle cerebral artery, have created confusion among clinicians, and this review has intended to clarify and highlight the available evidence that is pertinent to clinical management. A fetus who is small for gestational age is frequently defined as one with an estimated fetal weight of <10th percentile. This condition has been considered syndromic and has been frequently attributed to fetal growth restriction, a constitutionally small fetus, congenital infections, chromosomal abnormalities, or genetic conditions. Small for gestational age is not synonymous with fetal growth restriction, which is defined by deceleration of fetal growth determined by a change in fetal growth velocity. An abnormal umbilical artery Doppler pulsatility index reflects an increased impedance to flow in the umbilical circulation and is considered to be an indicator of placental disease. The combined finding of an estimated fetal weight of <10th percentile and abnormal umbilical artery Doppler velocimetry has been widely accepted as indicative of fetal growth restriction. Clinical studies have shown that the gestational age at diagnosis can be used to subclassify suspected fetal growth restriction into early and late, depending on whether the condition is diagnosed before or after 32 weeks of gestation. The early type is associated with umbilical artery Doppler abnormalities, whereas the late type is often associated with a low pulsatility index in the middle cerebral artery. A large randomized clinical trial indicated that in the context of early suspected fetal growth restriction, the combination of computerized cardiotocography and fetal ductus venosus Doppler improves outcomes, such that 95% of surviving infants have a normal neurodevelopmental outcome at 2 years of age. A low middle cerebral artery pulsatility index is associated with an adverse perinatal outcome in late fetal growth restriction; however, there is no evidence supporting its use to determine the time of delivery. Nonetheless, an abnormality in middle cerebral artery Doppler could be valuable to increase the surveillance of the fetus at risk. We propose that fetal size, growth rate, uteroplacental Doppler indices, cardiotocography, and maternal conditions (ie, hypertension) according to gestational age are important factors in optimizing the outcome of suspected fetal growth restriction.

The clinical significance of an estimated fetal weight below the 10th percentile: a comparison of outcomes of <5th vs 5th-9th percentile.

BACKGROUND: The association between small-for-gestational-age (birthweight <10th percentile for gestational age) and neonatal morbidity is well established. Yet, there is a paucity of data on the relationship between suspected small for gestational age (sonographic-estimated fetal weight <10th percentile) at 2 thresholds and subsequent neonatal morbidity. OBJECTIVE: The objective of this study was to determine the relationship between sonographic-estimated fetal weight <5th percentile vs 5-9th percentile and neonatal morbidity. STUDY DESIGN: This retrospective study involved 5 centers and included nonanomalous, singletons with sonographic-estimated fetal weight <10th percentile for gestational age who delivered from 2009-2012. Composite neonatal morbidity included respiratory distress syndrome, proven sepsis, intraventricular hemorrhage grade III or IV, necrotizing enterocolitis, thrombocytopenia, seizures, or death. Odd ratios were adjusted for center, maternal age, race, body mass index at first visit, smoking status, use of alcohol, use of drugs, and neonatal gender. RESULTS: Of 834 women with suspected small-for-gestational-age fetuses, 513 (62%) had sonographic-estimated fetal weight <5th percentile, and 321 (38%) had sonographic-estimated fetal weight of 5-9th percentile for gestational age. At delivery, 81% of women with a suspected small-for-gestational-age fetus had a confirmed small-for-gestational-age fetus. In the group with a sonographic-estimated fetal weight <5th percentile, 59% of neonates had birthweight <5th percentile; in the group with a sonographic-estimated fetal weight 5-9th percentile, 41% had birthweight <5th percentile, and 36% had birthweight at 5-9th percentile. Neonatal intensive care unit admission differed significantly for those fetuses at <5th percentile (29%) compared with those fetuses at 5-9th percentile (15%; P<.001). The composite neonatal morbidity among the sonographic-estimated fetal weight <5th percentile group was higher than the sonographic-estimated fetal weight of 5-9th percentile group (31% vs 13%; adjusted odds ratio, 2.41; 95% confidence interval, 1.53-3.80). Similar findings were noted when the analysis was limited to sonographic-estimated fetal weight within 28 days of delivery (adjusted odds ratio, 2.22; 95% confidence interval, 1.34-3.67). CONCLUSION: Eight of 10 suspected small-for-gestational-age fetuses had birthweight <10th percentile for gestational age; the prediction of actual birthweight was more accurate in the <5th percentile group. Neonates with sonographic-estimated fetal weight of <5th percentile were more likely to be admitted to the neonatal intensive care unit and have complications than were those neonates with sonographic-estimated fetal weight of 5-9th percentile.

Introduction: From fetal echocardiography to fetal cardiology: A journey of over half a century.

In this Special Issue of the Journal, 8 review articles that represent the new developments and applications of fetal echocardiography and fetal cardiology for diagnosis, prognosis, and treatment of fetal cardiovascular disease are included. The goal was to provide an updated review of the evidence for the current and emerging use of fetal echocardiography and cardiac magnetic resonance, improved diagnosis of challenging congenital heart disease, new tools for evaluation of fetal systolic and diastolic function, better prognosis and risk stratification of newborns with congenital heart diseases, and new and promising therapies for fetuses with cardiovascular disease.

A brief history of fetal echocardiography and its impact on the management of congenital heart disease.

Congenital heart disease (CHD), the most common congenital malformation, is associated with adverse outcome. Development of fetal echocardiography has made prenatal diagnosis of CHD a reality, and in the process revolutionized its management. This historical review briefly narrates this development over the decades focusing on the emergence of the primary modalities of fetal echocardiography comprised of the time-motion mode, two-dimensional B-mode, spectral Doppler, color Doppler, and three- and four-dimensional cardiac imaging. Collaboration between clinicians and engineers has been central to these advances. Also discussed are the accuracy and impact of fetal echocardiography on the management of CHD, and especially its role in the prenatal diagnosis of critical CHD in individualizing the management and improving the outcome. Despite these advances, most cases of CHD are not identified prenatally, emphasizing the continuing need for further technological and educational innovation and improvement.

Acute feTal behavioral Response to prenatal Yoga: a single, blinded, randomized controlled trial (TRY yoga).

BACKGROUND: In 2012, yoga was practiced by 20 million Americans, of whom 82% were women. A recent literature review on prenatal yoga noted a reduction in some pregnancy complications (ie, preterm birth, lumbar pain, and growth restriction) in those who practiced yoga; to date, there is no evidence on fetal response after yoga. OBJECTIVES: We aimed to characterize the acute changes in maternal and fetal response to prenatal yoga exercises using common standardized tests to assess the well-being of the maternal-fetal unit. STUDY DESIGN: We conducted a single, blinded, randomized controlled trial. Uncomplicated pregnancies between 28 0/7 and 36 6/7 weeks with a nonanomalous singleton fetus of women who did not smoke, use narcotics, or have prior experience with yoga were included. A computer-generated simple randomization sequence with a 1:1 allocation ratio was used to randomize participants into the yoga or control group. Women in the yoga group participated in a 1-time, 1 hour yoga class with a certified instructor who taught a predetermined yoga sequence. In the control group, each participant attended a 1-time, 1 hour PowerPoint presentation by an obstetrician on American Congress of Obstetricians and Gynecologists recommendations for exercise, nutrition, and obesity in pregnancy. All participants underwent pre- and postintervention testing, which consisted of umbilical and uterine artery Doppler ultrasound, nonstress testing, a biophysical profile, maternal blood pressure, and maternal heart rate. A board-certified maternal-fetal medicine specialist, at a different tertiary center, interpreted all nonstress tests and biophysical profile data and was blinded to group assignment and pre- or postintervention testing. The primary outcome was a change in umbilical artery Doppler systolic to diastolic ratio. Sample size calculations indicated 19 women per group would be sufficient to detect this difference in Doppler indices (alpha, 0.05; power, 80%). Data were analyzed using a repeated-measures analysis of variance, a χ(2), and a Fisher exact test. A value of P < .05 was considered significant. RESULTS: Of the 52 women randomized, 46 (88%) completed the study. There was no clinically significant change in umbilical artery systolic to diastolic ratio (P = .34), pulsatility index (P = .53), or resistance index (P = .66) between the 2 groups before and after the intervention. Fetal and maternal heart rate, maternal blood pressure, and uterine artery Dopplers remained unchanged over time. When umbilical artery indices were individually compared with gestational age references, there was no difference between those who improved or worsened between the groups. CONCLUSION: There was no significant change in fetal blood flow acutely after performing yoga for the first time in pregnancy. Yoga can be recommended for low-risk women to begin during pregnancy.

Down-regulation of placental neuropilin-1 in fetal growth restriction.

BACKGROUND: Fetal growth restriction (FGR) is associated with adverse outcomes extending from fetal to adult life, and thus, constitutes a major health care challenge. Fetuses with progressive growth restriction show increasing impedance in the umbilical artery flow, which may become absent during end-diastole. Absent end-diastolic flow (AEDF) is associated with adverse perinatal outcomes including stillbirths and perinatal asphyxia. Placentas from such pregnancies demonstrate deficient fetoplacental vascular branching. Current evidence, moreover, indicates an antiangiogenic state in maternal circulation in several pregnancy complications including preeclampsia, small-for-gestational-age births, fetal death, and preterm labor. The angiogenic mediators in maternal circulation are predominantly of placental origin. Information, however, on the role of specific proangiogenic and antiangiogenic mechanisms operating at the placental level remains limited. Elucidation of these placenta-specific angiogenic mechanisms will not only extend our understanding of the causal pathway for restricted fetal growth but may also lead to the development of biomarkers that may allow early recognition of FGR. OBJECTIVE: We sought to test the hypothesis that fetoplacental angiogenic gene expression is altered in pregnancies complicated with FGR and umbilical artery Doppler AEDF. STUDY DESIGN: Placental samples were collected from FGR pregnancies complicated with umbilical artery Doppler AEDF (study group, n = 7), and from uncomplicated pregnancies (control group, n = 7), all delivered by cesarean during the last trimester of pregnancy. Angiogenic oligonucleotide microarray analysis was performed and was corroborated by quantitative real-time polymerase chain reaction, Western blot analysis, and immunohistochemistry. The Student t test with Bonferroni correction was used with P < .05 considered statistically significant. Independent groups t test was used to analyze the immunostain intensity scores with a P < .05 considered statistically significant. RESULTS: Our microarray results showed that among several differentially expressed angiogenic genes in the growth-restricted group, only the down-regulation of neuropilin (NRP)-1 was most significant (P < .0007). Quantitative real-time polymerase chain reaction confirmed a significantly lower NRP-1 gene expression in the FGR group than in the control group (mean ± SD (ˆ)cycle threshold: 0.624 ± 0.55 and 1.325 ± 0.84, respectively, P = .04). Western blot validated significantly lower NRP-1 protein expression in the FGR group than in the control group (mean ± SD NRP-1/ß-actin ratio: 0.13 ± 0.04 and 0.34 ± 0.05, respectively, P < .001). Finally, immunohistochemistry of placental villi further corroborated a significantly decreased expression of NRP-1 in the FGR group (P = .006). CONCLUSION: The study demonstrated significant down-regulation of placental NRP-1 expression in FGR pregnancies complicated with AEDF in umbilical artery. As NRP-1 is known to promote sprouting angiogenesis, its down-regulation may be involved in the deficient vascular branching observed in FGR placentas suggesting the presence of an antiangiogenic state. Further studies may elucidate such a causal role and may lead to the development of novel diagnostic and therapeutic tools.

The Role of Nicotinamide Phosphoribosyltransferase in Pregnancy: A Review.

Nicotinamide phosphoribosyltransferase (NAMPT) was first reported in 1994 and has been explored in various human disease processes. However, until recently, very little has been done to define the role of NAMPT in pregnancy. NAMPT is a 52 kDa protein that has diverse functions in the human body, acting as a growth factor, cytokine, an enzyme, and an insulinomimetic agent. Initial studies examined NAMPT expression in fetal membranes and its effects on the amnion. Later research in nonpregnant studies showed an insulinomimetic effect, and attention focused on its role in gestational diabetes. In addition, as studies revealed NAMPT's function as an inflammatory cytokine, studies examined NAMPT in preeclampsia and fetal growth restriction. Several studies have confirmed that NAMPT is a marker of systemic infectious processes such as pyelonephritis and intrauterine infection. In this review, we present the current understanding of NAMPT's role in various pregnancy-related conditions as well as possible directions for future research.

Role of ultrasound in pre-eclampsia.

Pre-eclampsia (PE), defined as de novo hypertension (>140/90 mmHg) appearing after 20 weeks of gestation accompanied by proteinuria (>0.3 g/24 h), remains a major source of perinatal growth restriction, prematurity and death worldwide. Since its introduction practitioners have increasingly utilized fetal ultrasonography for the management of pre-eclampsia. Ultrasonographic diagnostic modalities including fetal biometric growth curves, the biophysical profile and umbilical artery Doppler have been used to detect fetal growth restriction and assess fetal wellbeing, respectively. Doppler studies of the middle cerebral and uterine arteries offer additional utility in the prediction of adverse pregnancy outcomes and as a potential screening test for pre-eclampsia. The purpose of this review was to explore the developments of ultrasound technology that have been relevant to the screening, diagnosis and management of pre-eclampsia.

Metabolomic identification of placental alterations in fetal growth restriction.

INTRODUCTION: Fetal growth restriction (FGR), viz., birth weight <10th percentile is a common pregnancy complication which increases the risk of adverse fetal and newborn outcomes. The placenta is the key organ for fetal growth as it controls oxygen and nutrient availability. This study aims to elucidate the mechanisms of and identify putative placental biomarkers for FGR using high-resolution metabolomics. METHODS: Placenta samples from 19 FGR cases and 30 controls were analyzed using proton magnetic resonance (1H NMR) spectroscopy and direct flow injection mass spectrometry with reverse-phase liquid-chromatography mass spectrometry (DI-LC-MS/MS). Significant concentration differences (p-value <.05) in 179 of the 220 metabolites were measured. RESULTS: Of the 179 metabolites, 176 (98.3%) had reduced placental levels in FGR cases. The best performing metabolite model: 3-hydroxybutyrate, glycine and PCaaC42:0 achieved an AUC (95% CI) = 0.912 (0.814-1.000) with a sensitivity of 86.7% and specificity of 84.2% for FGR detection. Metabolite set enrichment analysis (MSEA) revealed significant (p < .05) perturbation of multiple placental metabolite pathways including urea metabolism, ammonia recycling, porphyrin metabolism, bile acid biosynthesis, galactose metabolism and perturbed protein biosynthesis. CONCLUSION: The placental metabolic pathway analysis revealed abnormalities that are consistent with fetal hepatic dysfunction in FGR. Near global reduction of metabolite concentrations was found in the placenta from FGR cases and metabolites demonstrated excellent diagnostic accuracy for FGR detection.

Quality criteria for randomized controlled studies: obstetrical journal guidelines.

BACKGROUND: Most retractions of obstetrics and gynecology manuscripts are because of scientific misconduct. It would be preferable to prevent randomized controlled trials with scientific misconduct from ever appearing in the peer-reviewed scientific literature, rather than to have to retract them later. OBJECTIVE: This study aimed to evaluate the policies of obstetrics and gynecology and top medical journals in their author guidelines and electronic submission systems regarding prospective randomized controlled trial registration, ethics committee approval, research protocols, Consolidated Standards of Reporting Trial guidelines, and data sharing and to detect the most common quality criteria requested for randomized controlled trials in these journals. STUDY DESIGN: Author guidelines were identified via online Google searches from the websites of selected peer-reviewed medical journals. Journals in obstetrics and gynecology were selected from the list of journals with impact factors based on the Journal Citation Report released by Clarivate Analytics on June 29, 2020, focusing on those publishing original clinical research in obstetrics, in particular randomized controlled trials. In addition, 4 of the top impact factor peer-reviewed general medical journals publishing randomized controlled trials were included. The requirements for selected quality criteria for randomized controlled trials analyzed in the author guidelines for each journal were details of 5 general issues: prospective randomized controlled trial registration (4 subcategories), ethics committee approval (4 subcategories), research protocol (3 subcategories), Consolidated Standards of Reporting Trials guidelines (3 subcategories), and data sharing (3 subcategories). To evaluate the requirements within the electronic submission system, a mock submission of a randomized controlled trial was also done for each journal, and the same criteria were assessed on the online software for submission. The primary outcome was the overall percentage for each of the quality criteria that were listed as required within the author guidelines or required in the submission system among all journals. Planned subgroup analyses were top general medicine vs obstetrics and gynecology journals and top 4 obstetrics and gynecology vs other obstetrics and gynecology journals. RESULTS: Most studied peer-reviewed journals listed in their author guidelines 7 specific criteria for submission of randomized controlled trials: prospective registration and registration number, statement of ethical approval with name of approving committee and statement of informed consent, statement of adherence to Consolidated Standards of Reporting Trials guidelines, and data sharing statement. For most journals, the submission software did not require these or any other criteria for submission. There were minimal differences in criteria listed for top medical journals vs other obstetrics and gynecology journals and among top vs other obstetrics and gynecology journals. CONCLUSION: Prospective registration and registration number, statement of ethical approval with name of approving committee and statement of informed consent, statement of adherence to Consolidated Standards of Reporting Trials guidelines, and data sharing statement are the randomized controlled trial quality criteria requested by leading medical and obstetrics and gynecology journals. These obstetrics and gynecology journals agree to make, as much as possible, these criteria uniform and mandatory in author guidelines and also through improved submission software.

New horizons in Doppler ultrasound technology: relevance for obstetrical applications.

Technologic advances and clinical research have been extending the scope of Doppler sonography and have resulted in the emergence of new diagnostic tools that show significant promise in clinical applications. This article aims to review some of these developments that are relevant for obstetrical practice. One of the major recent technical developments in ultrasound imaging is the ability to assess tissue deformation. This has led to several clinical applications including functional echocardiography that allows evaluation of myocardial function using Doppler and speckle tracking techniques, and sonoelastography, which is ultrasound evaluation of tissue stiffness. Another relevant innovation is power Doppler imaging of regional perfusion. With further critical investigations, these emerging techniques may evolve into useful clinical tools.

Evidence-based approach to umbilical artery Doppler fetal surveillance in high-risk pregnancies: an update.

Antepartum fetal surveillance with Doppler ultrasound of umbilical artery has shown significant diagnostic efficacy in identifying fetal compromise in pregnancies complicated with fetal growth restriction and preeclampsia. Moreover, randomized clinical trials and their meta-analyses have shown its effectiveness in decreasing perinatal mortality (level I evidence). This is the only antepartum fetal test that has shown this level of effectiveness. There is no evidence that routine Doppler in low-risk pregnancies improves the outcome. It is recommended that umbilical artery Doppler should be the standard of practice in managing high-risk pregnancies complicated with fetal growth restriction and preeclampsia (level A recommendation). However, its use should be integrated with other current fetal monitoring tests (levels B and C recommendation). The overall management should also be guided by additional clinical considerations such as the gestational age, fetal and maternal status, and obstetrical conditions.

First-trimester metabolomic prediction of stillbirth.

Background: Stillbirth remains a major problem in both developing and developed countries. Omics evaluation of stillbirth has been highlighted as a top research priority. Objective: To identify new putative first-trimester biomarkers in maternal serum for stillbirth prediction using metabolomics-based approach. Methods: Targeted, nuclear magnetic resonance (NMR) and mass spectrometry (MS), and untargeted liquid chromatography-MS (LC-MS) metabolomic analyses were performed on first-trimester maternal serum obtained from 60 cases that subsequently had a stillbirth and 120 matched controls. Metabolites by themselves or in combination with clinical factors were used to develop logistic regression models for stillbirth prediction. Prediction of stillbirths overall, early (<28 weeks and <32 weeks), those related to growth restriction/placental disorder, and unexplained stillbirths were evaluated. Results: Targeted metabolites including glycine, acetic acid, L-carnitine, creatine, lysoPCaC18:1, PCaeC34:3, and PCaeC44:4 predicted stillbirth overall with an area under the curve [AUC, 95% confidence interval (CI)] = 0.707 (0.628-0.785). When combined with clinical predictors the AUC value increased to 0.740 (0.667-0.812). First-trimester targeted metabolites also significantly predicted early, unexplained, and placental-related stillbirths. Untargeted LC-MS features combined with other clinical predictors achieved an AUC (95%CI) = 0.860 (0.793-0.927) for the prediction of stillbirths overall. We found novel preliminary evidence that, verruculotoxin, a toxin produced by common household molds, might be linked to stillbirth. Conclusions: We have identified novel biomarkers for stillbirth using metabolomics and demonstrated the feasibility of first-trimester prediction.

Correlation of obesity and osteoporosis: effect of fat mass on the determination of osteoporosis.

It was previously believed that obesity and osteoporosis were two unrelated diseases, but recent studies have shown that both diseases share several common genetic and environmental factors. Body fat mass, a component of body weight, is one of the most important indices of obesity, and a substantial body of evidence indicates that fat mass may have beneficial effects on bone. Contrasting studies, however, suggest that excessive fat mass may not protect against osteoporosis or osteoporotic fracture. Differences in experimental design, sample structure, and even the selection of covariates may account for some of these inconsistent or contradictory results. Despite the lack of a clear consensus regarding the impact of effects of fat on bone, a number of mechanistic explanations have been proposed to support the observed epidemiologic and physiologic associations between fat and bone. The common precursor stem cell that leads to the differentiation of both adipocytes and osteoblasts, as well the secretion of adipocyte-derived hormones that affect bone development, may partially explain these associations. Based on our current state of knowledge, it is unclear whether fat has beneficial effects on bone. We anticipate that this will be an active and fruitful focus of research in the coming years.

Effect of hypoxia on protein tyrosine phosphatase activity and expression of protein tyrosine phosphatases PTP-1B, PTP-SH1 and PTP-SH2 in the cerebral cortex of guinea pig fetus.

The present study tested the hypothesis that the hypoxia in utero results in decreased protein tyrosine phosphatase (PTP) activity in cytosolic and membrane fractions and increased expression of PTPs (PTP-1B, PTP-SH1 and PTP-SH2) in the cytosol and the membrane fraction of the cerebral cortex of guinea pig fetus. In addition, we hypothesize that the increased expression is mediated by nitric oxide (NO). To test this hypothesis, PTP activity in cytosol and cell membrane, and expression in the cytosol and membrane fraction were measured in the cerebral cortex of normoxic, hypoxic and L-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthase (NOS), pretreated hypoxic (L-NAME+Hx) guinea pig fetuses. PTP activity in the cytosolic and membrane fractions was significantly lower in the Hx group as compared to the Nx group. The density of cytosolic PTP-1B, cytosolic PTP-SH1 and PTP-SH2 was increased in the Hx group and this increase was prevented in the L-NAME+Hx group. The data show that pretreatment with L-NAME, an inhibitor of NOS, prevents the hypoxia-induced increased expression of PTP-1B, PTP-SH1 and PTP-SH2 in the membrane and cytosolic fractions of the cerebral cortex of the guinea pig fetus. We conclude that the decrease in PTP activity during hypoxia is not due to protein modification of PTP and due to alteration in PTP expression.

Activation of p38 mitogen-activated protein kinase (p38 MAPK), extracellular signal-regulated kinase (ERK) and c-jun N-terminal kinase (JNK) during hypoxia in cerebral cortical nuclei of guinea pig fetus at term: role of nitric oxide.

Previously we have shown that cerebral tissue hypoxia results in generation of nitric oxide (NO) free radicals as well as increased expression of mitogen-activated protein kinase like extracellular signal-regulated kinase (ERK) and c-jun N-terminal kinase (JNK). The present study tested the hypothesis that administration of l-nitro-l-arginine methyl ester (L-NAME), a NOS inhibitor, prior to hypoxia prevents the hypoxia-induced activation of p38 mitogen-activated protein kinase (p38 MAPK), extracellular signal-regulated kinase (ERK) and c-jun N-terminal kinase (JNK) and in the cerebral cortex of the term guinea pig fetus. To test this hypothesis normoxic (Nx, n=6), hypoxic (Hx, n=7) and hypoxic pretreated with l-NAME (Hx+L-NAME, n=6) guinea pig fetuses at 60 days gestation were studied to determine the phosphorylated p38, ERK and JNK. Hypoxia was induced by exposing pregnant guinea pigs to FiO2 of 0.07 for 1h. l-NAME (30mg/kg i.p.) was administered to pregnant mothers 60min prior to hypoxia. Cerebral tissue hypoxia was documented biochemically by determining the tissue levels of ATP and phosphocreatine (PCr). Neuronal nuclei were isolated, purified and proteins separated using 12% SDS-PAGE, and then probed with specific phosphorylated ERK, JNK and p38 antibodies. Protein bands were detected by enhanced chemiluminescence, analyzed by imaging densitometry and expressed as absorbance (ODxmm2). The relative level of p-p38 was 51.41+/-9.80 (Nx), 173.67+/-3.63 (Hx), 58.56+/-3.40 (Hx+L-NAME), p<0.05 vs. Hx. The relative level p-ERK was 44.91+/-4.20 (Nx), 135.12+/-17.02 (Hx), 58.37+/-9.5 (Hx+L-NAME), p<0.05 vs. Hx. The relative level of p-JNK was 34.86+/-6.77 (Nx), 97.36+/-19.24 (Hx), 46.65+/-12.81 (Hx+L-NAME), p<0.05 vs. Hx. The data show that administration of l-NAME prior to hypoxia decreased the relative level of phosphorylated p38, ERK and JNK at term gestation. Since a NOS inhibitor prevented the hypoxia-induced phosphorylation of p38, ERK and JNK, we conclude that the hypoxia-induced activation of p38, ERK and JNK in the cerebral cortical nuclei of guinea pig fetus at term is NO-mediated. We speculate that NO-mediated modification of cysteine residue leading to inhibition of MAP kinase phosphatases results in increased activation of p38, ERK and JNK in the guinea pig fetus at term.

A vision for an International Society for Fetal and Perinatal Cardiovascular Disease.

PURPOSE OF REVIEW: The purpose of this review is to explain why it is now time to create an International Society for Fetal and Perinatal Cardiovascular Disease. RECENT FINDINGS: Rapid advances in four domains that involve the professionals caring for patients with congenital cardiac disease all point to the fact that it is now time to create an International Society for Fetal and Perinatal Cardiovascular Disease: fetal diagnosis - the improved ability to diagnose prenatal cardiovascular disease due to education and improved ultrasound technology; subspecialization--the development of perinatal cardiology as a true subspecialty of the professions of pediatric cardiology and perinatology; analysis of outcomes--the multidisciplinary international efforts in the areas of nomenclature and databases for the analysis of outcomes of treatments for patients with congenitally malformed hearts, efforts that span traditional geographic and subspecialty boundaries; globalization - the rapidly evolving global organization of professionals caring for patients with congenital heart disease. SUMMARY: Healthcare professionals caring for the pregnant woman and fetus with congenital cardiac disease would be enthusiastic about the creation of an International Society for Fetal and Perinatal Cardiovascular Disease in order to achieve multiple objectives: to discuss the management of prenatal and perinatal cardiovascular disease (not exclusively cardiac malformations); to benefit from educational programs covering prenatal and perinatal physiology and pathophysiology, clinical and technical topics, as well as genetic, ethical, and psychosocial aspects of this relatively new discipline; and finally to share our basic science, translational, and clinical research interests.

Complementary and Alternative Medicine Use in Modern Obstetrics: A Survey of the Central Association of Obstetricians & Gynecologists Members.

The use of complementary and alternative medicine during pregnancy is currently on the rise. A validated survey was conducted at the Central Association of Obstetrician and Gynecologists annual meeting to evaluate the knowledge, attitude, and practice of general obstetricians and gynecologists and maternal-fetal medicine specialists in America. We obtained 128 responses: 73 electronically (57%) and 55 via the paper survey (43%). Forty-five percent reported personally using complementary and alternative medicine and 9% of women respondents used complementary and alternative medicine during pregnancy. Overall, 62% had advised their patients to utilize some form of complementary and alternative medicine in pregnancy. Biofeedback, massage therapy, meditation, and yoga were considered the most effective modalities in pregnancy (median [semi-interquartile range] = 2 [0.5]). Maternal-fetal medicine specialists were significantly more likely to disagree on the use of complementary and alternative medicine for risk reduction of preterm birth compared to obstetricians and gynecologists ( P = .03). As the use of complementary and alternative medicine continues to rise in reproductive-age women, obstetricians will play an integral role in incorporating complementary and alternative medicine use with conventional medicine.

MC-PPEA as a new and more potent inhibitor of CLP-induced sepsis and pulmonary inflammation than FK866.

Our previous study indicated that overexpression of nicotinamide phosphoribosyltransferase (NAMPT) aggravated acute lung injury, while knockdown of NAMPT expression attenuated ventilator-induced lung injury. Recently, we found that meta-carborane-butyl-3-(3-pyridinyl)-2E-propenamide (MC-PPEA, MC4), in which the benzoylpiperidine moiety of FK866 has been replaced by a carborane, displayed a 100-fold increase in NAMPT inhibition over FK866. Here, we determined the effects of MC4 and FK866 on cecal ligation and puncture (CLP) surgery-induced sepsis in C57BL/6J mice. MC4 showed stronger inhibitory effects than FK866 on CLP-induced mortality, serum tumor necrosis factor α (TNFα) levels, pulmonary myeloperoxidase activity, alveolar injury, and interleukin 6 and interleukin1ß messenger RNA levels. In vitro cell permeability and electric cell-substrate impedance sensing assays demonstrated that MC4 inhibited TNFα- and thrombin-mediated pulmonary endothelial cell permeability better than FK866. MC4 also exerted more potent effects than FK866, at concentrations as low as 0.3 nM, to attenuate TNFα-mediated intracellular cytokine expression, nicotinamide adenine dinucleotide (NAD+) and its reduced form NADH levels, and nuclear factor kappa B p65 phosphorylation and nuclear translocation in A549 cells. Our results strongly suggest that the newly developed MC4 is a more potent suppressor of CLP-induced pulmonary inflammation and sepsis than FK866, with potential clinical application as a new treatment agent for sepsis and inflammation.

United States multicenter clinical usage study of the STAN 21 electronic fetal monitoring system.

OBJECTIVE: The fetal electrocardiogram system for electronic fetal monitoring (EFM) (STAN S21, Neoventa Medical, Moelndal, Sweden) has led to improved perinatal outcomes in other countries. We aimed to assess the ability of United States (US) obstetricians to use this system appropriately for intrapartum care. STUDY DESIGN: A prospective nonrandomized trial was conducted in 6 sites. Enrollment required a singleton vertex fetus, >36 weeks' gestation, with indications for direct fetal monitoring during first stage of labor. Appropriate use was measured by negative predictive value (NPV) of nonintervention for fetuses with nonreassuring fetal heart rate (FHR) patterns, normal STAN readings, and normal neonatal outcomes with umbilical cord arterial pH >7.12; and percent agreement (PA) for intervention decisions with 3 STAN experts who conducted retrospective case reviews blinded to outcome. RESULTS: Five hundred and thirty patients were enrolled. An NPV of 95.2% was achieved while PA between investigators and STAN experts was 84%, and 90%, for intervention and nonintervention, respectively. No fetus with metabolic acidosis requiring intervention was missed by US clinicians. CONCLUSION: US clinicians used the STAN system appropriately in a manner similar to that of experienced STAN users.