Evaluation of Prenatal Hepatitis C Virus Prevalence Using Universal Screening, and Linkage to Care in a Real-World Setting in Ontario.

OBJECTIVES: International infectious disease/obstetrical societies have recently recommended universal hepatitis C virus (HCV) prenatal screening and these same recommendations are forthcoming in Canada. At present, there is no formal analysis of universal HCV screening or linkage to care of pregnant people in Ontario. The objectives of our study were to determine the seroprevalence of HCV using 2 different methods to evaluate universal screening, as well as identify opportunities that may improve linkage to care. METHODS: To assess seroprevalence in a large urban area, we aimed to test 12 000 de-identified samples submitted for prenatal HIV testing in the catchment area of Toronto Public Health for HCV antibodies. Then, to assess the seroprevalence as well as the operational impact and follow-up in a real-world setting, we completed a Quality Improvement Project (QIP) for 1 year at a large tertiary care obstetrical centre in London, Ontario. RESULTS: From 2019 to 2021, 11 999 de-identified samples were screened from Toronto with a seroprevalence of 0.40 (95% CI 0.29-0.53). In London, 5771 people were screened in 2021 with a seroprevalence of 0.55% (95% CI 0.38-0.78). Taken together, those aged 26-35 years had the highest positivity; in the QIP, 9% had no documented risk factor, and 59% of individuals were not linked to the next step in HCV care. CONCLUSIONS: HCV prenatal seroprevalence in Ontario is comparable to hepatitis B virus, and ∼15-30-fold higher than HIV. Diagnosis in pregnancy is critical to facilitate referrals for treatment between pregnancies and could increase screening among children born to positive women.

Antiviral Inflammation during Early Pregnancy Reduces Placental and Fetal Growth Trajectories.

Many viruses are detrimental to pregnancy and negatively affect fetal growth and development. What is not well understood is how virus-induced inflammation impacts fetal-placental growth and developmental trajectories, particularly when inflammation occurs in early pregnancy during nascent placental and embryo development. To address this issue, we simulated a systemic virus exposure in early pregnant rats (gestational day 8.5) by administering the viral dsRNA mimic polyinosinic:polycytidylic acid (PolyI:C). Maternal exposure to PolyI:C induced a potent antiviral response and hypoxia in the early pregnant uterus, containing the primordial placenta and embryo. Maternal PolyI:C exposure was associated with decreased expression of the maternally imprinted genes Mest, Sfrp2, and Dlk1, which encode proteins critical for placental growth. Exposure of pregnant dams to PolyI:C during early pregnancy reduced fetal growth trajectories throughout gestation, concomitant with smaller placentas, and altered placental structure at midgestation. No detectable changes in placental hemodynamics were observed, as determined by ultrasound biomicroscopy. An antiviral response was not evident in rat trophoblast stem (TS) cells following exposure to PolyI:C, or to certain PolyI:C-induced cytokines including IL-6. However, TS cells expressed high levels of type I IFNR subunits (Ifnar1 and Ifnar2) and responded to IFN-⍺ by increasing expression of IFN-stimulated genes and decreasing expression of genes associated with the TS stem state, including Mest IFN-⍺ also impaired the differentiation capacity of TS cells. These results suggest that an antiviral inflammatory response in the conceptus during early pregnancy impacts TS cell developmental potential and causes latent placental development and reduced fetal growth.

Quantification of 1.5 T T1 and T2* Relaxation Times of Fetal Tissues in Uncomplicated Pregnancies.

BACKGROUND: Despite its many advantages, experience with fetal magnetic resonance imaging (MRI) is limited, as is knowledge of how fetal tissue relaxation times change with gestational age (GA). Quantification of fetal tissue relaxation times as a function of GA provides insight into tissue changes during fetal development and facilitates comparison of images across time and subjects. This, therefore, can allow the determination of biophysical tissue parameters that may have clinical utility. PURPOSE: To demonstrate the feasibility of quantifying previously unknown T1 and T2* relaxation times of fetal tissues in uncomplicated pregnancies as a function of GA at 1.5 T. STUDY TYPE: Pilot. POPULATION: Nine women with singleton, uncomplicated pregnancies (28-38 weeks GA). FIELD STRENGTH/SEQUENCE: All participants underwent two iterative decomposition of water and fat with echo asymmetry and least-squares estimation (IDEAL-IQ) acquisitions at different flip angles (6° and 20°) at 1.5 T. ASSESSMENT: Segmentations of the lungs, liver, spleen, kidneys, muscle, and adipose tissue (AT) were conducted using water-only images and proton density fat fraction maps. Driven equilibrium single pulse observation of T1 (DESPOT1 ) was used to quantify the mean water T1 of the lungs, intraabdominal organs, and muscle, and the mean water and lipid T1 of AT. IDEAL T2* maps were used to quantify the T2* values of the lungs, intraabdominal organs, and muscle. STATISTICAL TESTS: F-tests were performed to assess the T1 and T2* changes of each analyzed tissue as a function of GA. RESULTS: No tissue demonstrated a significant change in T1 as a function of GA (lungs [P = 0.89]; liver [P = 0.14]; spleen [P = 0.59]; kidneys [P = 0.97]; muscle [P = 0.22]; AT: water [P = 0.36] and lipid [P = 0.14]). Only the spleen and muscle T2* showed a significant decrease as a function of GA (lungs [P = 0.67); liver [P = 0.05]; spleen [P < 0.05]; kidneys [P = 0.70]; muscle [P < 0.05]). DATA CONCLUSION: These preliminary data suggest that the T1 of the investigated tissues is relatively stable over 28-38 weeks GA, while the T2* change in spleen and muscle decreases significantly in that period. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY STAGE: 2.

Water-fat magnetic resonance imaging of adipose tissue compartments in the normal third trimester fetus.

BACKGROUND: Assessment of fetal adipose tissue gives information about the future metabolic health of an individual, with evidence that the development of this tissue has regional heterogeneity. OBJECTIVE: To assess differences in the proton density fat fraction (PDFF) between fetal adipose tissue compartments in the third trimester using water-fat magnetic resonance imaging (MRI). MATERIALS AND METHODS: Water-fat MRI was performed in a 1.5-T scanner. Fetal adipose tissue was segmented into cheeks, thorax, abdomen, upper arms, forearms, thighs and lower legs. PDFF and R2* values were measured in each compartment. RESULTS: Twenty-eight women with singleton pregnancies were imaged between 28 and 38 weeks of gestation. At 30 weeks' gestation (n=22), the PDFF was statistically different between the compartments (P<0.0001), with the highest PDFF in cheeks, followed by upper arms, thorax, thighs, forearms, lower legs and abdomen. There were no statistical differences in the rate of PDFF change with gestational age between the white adipose tissue compartments (P=0.97). Perirenal brown adipose tissue had a different PDFF and R2* compared to white adipose tissue, while the rate of R2* change did not significantly change with gestational age between white adipose tissue compartments (P=0.96). CONCLUSION: Fetal adipose tissue accumulates lipids at a similar rate in all white adipose tissue compartments. PDFF variances between the compartments suggest that accumulation begins at different gestational ages, starting with cheeks, followed by extremities, trunk and abdomen. Additionally, MRI was able to detect differences in the PDFF between fetal brown adipose tissue and white adipose tissue.

Peripartum hyperhemolysis prophylaxis and management in sickle cell disease: A case report and narrative review.

BACKGROUND: Sickle cell disease (SCD) is associated with hematologic complications including delayed hemolytic transfusion reactions (DHTRs) and pregnancy-related morbidity and mortality. Hyperhemolysis syndrome (HS) is the most severe form of DHTR in patients with SCD, in which both transfused and native red blood cells are destroyed. Further transfusions are avoided after a history of HS. Immunosuppressive agents can be used as prophylaxis against life-threatening hemolysis when transfusion is necessary. There is a paucity of evidence for the use of HS prophylaxis before transfusions, the continuation of hydroxyurea (HU) in lieu of chronic transfusion, and the use of erythropoiesis-stimulating agents (ESA) in pregnant SCD patients. CASE REPORT: We present a case of a pregnant patient with SCD and a previous history of HS. HS prophylaxis was given before transfusion with corticosteroids, intravenous immunoglobulin, and rituximab. In addition, HU was continued during pregnancy to control SCD, along with the use of concomitant ESA to maintain adequate hemoglobin levels and avoid transfusion. We describe a multidisciplinary approach to pregnancy and delivery management including tailored anesthetic and obstetric planning. CONCLUSION: This is the first published case of HS prophylaxis in a pregnant SCD patient, with good maternal and fetal outcomes after transfusion. HU and ESAs were able to control SCD and mitigate anemia in lieu of prophylactic transfusions during pregnancy. Further prospective studies are necessary to elucidate the ideal management of pregnant SCD patients with a history of HS or other contraindications to chronic transfusion.

Maternal obesity reduces placental autophagy marker expression in uncomplicated pregnancies.

AIM: Obesity has been associated with changes in autophagy and its increasing prevalence among pregnant women is implicated in higher rates of placental-mediated complications of pregnancy such as pre-eclampsia and intrauterine growth restriction. Autophagy is involved in normal placentation, thus changes in autophagy may lead to impaired placental function and development. The aim of this study was to investigate the connection between obesity and autophagy in the placenta in otherwise uncomplicated pregnancies. METHODS: Immunohistochemistry and western blot analysis were done on placental and omental samples from obese (body mass index [BMI] ≥30 kg/m2 ) and normal weight (BMI <25 kg/m2 ) pregnant women with singleton pregnancies undergoing planned Caesarean delivery without labor at term. Samples were analyzed for autophagic markers LC3B and p62 in the peripheral, middle and central regions of the placenta and in omental adipocytes, milky spots and vasculature. RESULTS: As pre-pregnancy BMI increased, there was an increase in both placental and fetal weight as well as decreased levels of LC3B in the central region of the placenta (P = 0.0046). Within the obese patient group, LC3B levels were significantly decreased in the placentas of male fetuses compared to females (P < 0.0001). Adipocytes, compared to milky spots and vasculature, had lower levels of p62 (P = 0.0127) and LC3B (P = 0.003) in obese omenta and lower levels of LC3B in control omenta (P = 0.0071). CONCLUSION: Obesity leads to reduced placental autophagy in uncomplicated pregnancies; thus, changes in autophagy may be involved in the underlying mechanisms of obesity-related placental diseases of pregnancy.

Respiratory Morbidity in Late Preterm and Term Babies Born by Elective Caesarean Section.

OBJECTIVE: This study sought to determine the incidence and severity of respiratory morbidity among late preterm and term babies born by elective Caesarean section (CS) in London, Ontario. METHODS: A retrospective chart review was conducted of all elective CSs performed at or beyond 360 weeks gestation from June 2010 to June 2014 at London Health Sciences Centre and St. Joseph's Health Care (Canadian Task Force Classification II-2). RESULTS: The main indications for elective CS were previous CS (59.3%) and malpresentation (24.2%). The majority of elective CSs were performed at 38 weeks (34.1%) and 39 weeks (40.1%). Although only 3.7% of babies born by elective CS were found to have respiratory morbidity, 85% of these babies were admitted to the neonatal intensive care unit (NICU), and 15% required additional observation through a triage period. The relative risk of respiratory morbidity with elective CS at ≤386 weeks compared with ≥390 weeks was 2.14 (P = 0.0110). Only 3.5% of patients received antenatal steroids. There was an increased level of intervention among the babies admitted to the NICU for respiratory morbidity; 47.8%, 19.6%, 60.8%, and 15.25% required oxygen supplement, bag and mask, continuous positive airway pressure, and intubation with mechanical ventilation, respectively. CONCLUSION: The risk of respiratory morbidity was significantly higher following elective CS before 39 weeks gestation. This resulted in increased length of stay and increased requirements for intravenous lines, blood draws, and exposure to antibiotics. This study provides further evidence that uncomplicated elective CS should be performed at ≥39 weeks, and interventions, such as preoperative antenatal steroid administration, may be considered if elective CS is medically indicated before 39 weeks.

Decorin over-expression by decidual cells in preeclampsia: a potential blood biomarker.

BACKGROUND: Decorin, a leucine-rich proteoglycan that is produced by decidual cells, limits invasion and endovascular differentiation of extravillous trophoblast cells during early placentation by binding to multiple tyrosine kinase receptors, in particular, vascular endothelial growth factor receptor-2. OBJECTIVE: Because many studies have reported an association between poor trophoblast invasion and endovascular differentiation with preeclampsia, the studies reported here tested (1) whether decorin over-expression in the chorionic villi and/or basal decidua is associated with preeclampsia and, if so, (2) whether this association results in a hypoinvasive placenta, and (3) whether elevated plasma decorin concentration in the second trimester is a predictive biomarker for preeclampsia. STUDY DESIGN: Decorin messenger RNA expression was measured with quantitative polymerase chain reaction at the tissue level and with in situ hybridization at the cellular level using (35)S-labeled antisense complimentary RNA probe in placentas from healthy control subjects and subjects with preeclampsia (14 each, 23-40 weeks of gestation). Tissue sections of the same placentas were also immunostained for decorin protein. A decorin over-expressing human endometrial stromal cell line was tested for invasion-regulatory effects on an invasive first-trimester extravillous trophoblast cell line HTR-8/SVneo plated in cocultures that were separated by a semipermeable membrane. Furthermore, we conducted retrospective measurements of plasma decorin levels during the second trimester (15-18 weeks of gestation) in a cohort of 28 body mass index-matched pairs of control subjects and subjects with preeclampsia before the onset of clinical disease. RESULTS: First, decorin messenger RNA expression at the cellular level measured with in situ hybridization exhibited profoundly higher expression levels in basal plate decidual cells within the placentas from preeclamptic subjects than those from control subjects at all gestational ages, whereas no difference between the 2 subject groups was noted in villus mesenchymal cells. Similarly decorin messenger RNA expression at the tissue level in chorionic villi (primarily resulting from fetally derived mesenchymal cells) did not differ significantly between control and preeclampsia placentas. These findings were validated with immunostaining for decorin protein. Second, knocking down decorin gene in a decorin over-expressing endometrial cell line (used as an in vitro surrogate of decorin over-expressing decidual cells) in cocultures with extravillous trophoblast cells abrogated its invasion-restraining actions on trophoblast cells, which indicated paracrine contribution of decorin over-expressing decidua to the poor trophoblast invasiveness in situ. Finally, retrospective measurement of plasma decorin levels during the second trimester in 28 body mass index-matched pairs of control subjects and subjects with preeclampsia revealed elevated plasma decorin levels in all subjects with preeclampsia in all body mass index groups. A receiver operating characteristic curve analysis revealed strong diagnostic performance of plasma decorin in the prediction of preeclampsia status. Although there was no significant gestational age-related change in decorin levels during the second trimester in control or subjects with preeclampsia, we found that plasma decorin had a significant inverse relationship with body mass index or bodyweight. CONCLUSION: We conclude that decorin over-expression by basal decidual cells is associated with hypoinvasive phenotype and poor endovascular differentiation of trophoblast cells in preeclampsia and that elevated plasma decorin concentration is a potential predictive biomarker for preeclampsia before the onset of clinical signs.

Designing a Multidisciplinary Cardio-obstetrics Curriculum for General Cardiology and Obstetrics Residents: A National Survey of Educational Needs.

Background: The increasing and potentially preventable cardiac events in pregnant patients have led to calls to enhance multidisciplinary cardio-obstetrics education. To design a multidisciplinary cardio-obstetrics curriculum for general cardiology and obstetrics and gynecology (OBGYN) residents, we need to define educational needs from the perspectives of both cardiology and OBGYN residents. Our study characterizes the educational needs of Canadian cardiology and OBGYN residents. Methods: Canadian cardiology and OBGYN residents were surveyed on clinical exposures, perceived needs for topics, unperceived needs for topics (multiple-choice questions) and preferences for educational formats. High priorities were defined as ≥ 50% of responses indicating a perceived need or ≥ 50% indicating an unperceived need. Results: A total of 154 residents participated (cardiology n = 44, OBGYN n = 110). Residents reported insufficient clinical exposure to nearly all cardiac disorders, with 33% of exposures occurring in multidisciplinary contexts. All topics aside from gestational hypertension were rated as high priority on perceived needs by both specialties. High-priority unperceived needs were congenital heart disease (both specialties), pre-existing acquired heart disease (both specialties), medication safety (OBGYN), peripartum management (OBGYN), and pregnancy-related heart disease (OBGYN). Cardiology and OBGYN residents shared preferences for in-person simulation, virtual simulation, and online modules. Conclusions: Residents in both specialties reported low clinical exposure to most cardiac disorders during pregnancy, identified high-priority perceived needs in multiple topics, and shared 2 high-priority unperceived needs. OBGYN residents identified 3 additional high-priority unperceived needs. These data can inform design of multidisciplinary cardio-obstetrics curricula for general cardiology and OBGYN residents.

Contexte: L'augmentation du nombre d'événements cardiaques potentiellement évitables chez les patientes enceintes a conduit à des appels pour renforcer la formation multidisciplinaire en cardio-obstétrique. Afin de concevoir un programme d'études multidisciplinaires en cardio-obstétrique pour les résidents en cardiologie générale et en obstétrique et gynécologie (OBGYN), nous devons définir les besoins éducatifs du point de vue des résidents en cardiologie et en OBGYN. Notre étude caractérise les besoins éducatifs des résidents canadiens en cardiologie et en OBGYN. Méthodes: Les résidents canadiens en cardiologie et en OBGYN ont été interrogés sur leurs expositions cliniques, les besoins perçus et non perçus en matière de thématique à aborder (questions à choix multiples) et leurs préférences en matière de formats éducatifs. Les priorités élevées ont été définies comme représentant ≥ 50 % des réponses indiquant un besoin perçu ou ≥ 50 % indiquant un besoin non perçu. Résultats: Cent cinquante-quatre résidents ont participé (cardiologie n = 44, OBGYN n = 110). Les résidents ont signalé une exposition clinique insuffisante pour presque tous les troubles cardiaques, 33 % des expositions se produisant dans des contextes multidisciplinaires. Toutes les thématiques, à l'exception de l'hypertension gestationnelle, ont été jugées hautement prioritaires en ce qui concerne les besoins perçus par les deux spécialités. Les besoins non perçus comme hautement prioritaires comprenaient les cardiopathies congénitales (les deux spécialités), les cardiopathies acquises préexistantes (les deux spécialités), la sécurité des médicaments (OBGYN), la gestion du péripartum (OBGYN) et les cardiopathies liées à la grossesse (OBGYN). Les résidents en cardiologie et en OBGYN partageaient des préférences pour les simulations en personne, les simulations virtuelles et les modules de formation en ligne. Conclusions: Les résidents des deux spécialités ont rapporté une faible exposition clinique à la plupart des troubles cardiaques pendant la grossesse, ont identifié des besoins perçus comme hautement prioritaires dans plusieurs domaines, et ont partagé 2 besoins non perçus comme hautement prioritaires. Les résidents en OBGYN ont identifié 3 autres besoins non perçus comme hautement prioritaires. Ces données peuvent éclairer la conception de programmes d'études multidisciplinaires en cardio-obstétrique pour les résidents en cardiologie générale et en OBGYN.

Fetal sex impacts birth to placental weight ratio and umbilical cord oxygen values with implications for regulatory mechanisms.

BACKGROUND: We determined the effect of fetal sex on birth/placental weight and umbilical vein and artery oxygen values with implications for placental efficiency and regulatory mechanisms underlying fetal-placental growth differences. METHODS: A hospital database was used to obtain birth/placental weight, cord PO2 and other information on patients delivering between Jan 1, 1990 and Jun 15, 2011 with GA > 34 weeks (N = 69,836). Oxygen saturation was calculated from the cord PO2 and pH data, while fractional O2 extraction was calculated from the oxygen saturation data. The effect of fetal sex on birth/placental weight, cord PO2, O2 saturation, and fractional O2 extraction was examined in all patients adjusting for pregnancy and labor/delivery covariates, and in a subset of low-risk patients. RESULTS: Birth/placental weights were lower in females indicating decreased placental efficiency. Umbilical vein oxygen values were higher in females attributed to increased uterine blood flow, while artery oxygen values were lower in females attributed to decreased hemoglobin and umbilical blood flow, and increased oxygen consumption. Fetal O2 extraction was increased in females confirming increased O2 consumption relative to delivery. CONCLUSIONS: Sex-related differences in uterine/umbilical blood flows, placental development, and fetal O2 consumption can be linked to the differences observed in cord oxygen. The lower umbilical artery oxygen in females as a measure of systemic oxygenation signaling growth could account for their decreased birth weights, while slower development in female placentae could account for their lower placental weights, which could be differentially effected contributing to their lower birth/placental weights.

Highlighting the Mechanistic Relationship Between Perinatal Depression and Preeclampsia: A Scoping Review.

Background: Although there is scientific literature supporting an association between depression and preeclampsia (PE), little is known about the underlying mechanistic pathways that may explain these observed associations. Thus, this study aimed to outline the relationship between depression and PE, and to highlight the underlying cardiovascular and metabolic risk factors that are common to both. Methods: A scoping review of the literature was conducted in Medline, Scopus, and Web of Science. Results: From 706 articles initially identified, 23 articles met the inclusion criteria and were included in this review. Although some studies reported a positive association between PE and postpartum depressive symptoms, challenges comparing different methodologies, measurement instruments and when measurements were administered, and patient populations do not permit a decisive conclusion. In addition, very few studies addressed potential underlying mechanisms that may be contributing to observed associations; thus, a secondary search was conducted to identify cardiovascular and metabolic risk factors that are common to both depression and PE. Conclusion: The cardiovascular and metabolic risk factors (i.e., increased inflammation and oxidative stress and decreased vascular and endothelial function) common to both depression and PE suggest that these factors may contribute as underlying mechanisms in both conditions. These similarities underscore the importance to better understand these mechanisms so preventative and therapeutic strategies could be developed to improve maternal health.

Effects of Maternal Obesity and Gestational Diabetes Mellitus on the Placenta: Current Knowledge and Targets for Therapeutic Interventions.

Obesity and gestational diabetes mellitus (GDM) are becoming more common among pregnant women worldwide and are individually associated with a number of placenta-mediated obstetric complications, including preeclampsia, macrosomia, intrauterine growth restriction and stillbirth. The placenta serves several functions throughout pregnancy and is the main exchange site for the transfer of nutrients and gas from mother to fetus. In pregnancies complicated by maternal obesity or GDM, the placenta is exposed to environmental changes, such as increased inflammation and oxidative stress, dyslipidemia, and altered hormone levels. These changes can affect placental development and function and lead to abnormal fetal growth and development as well as metabolic and cardiovascular abnormalities in the offspring. This review aims to summarize current knowledge on the effects of obesity and GDM on placental development and function. Understanding these processes is key in developing therapeutic interventions with the goal of mitigating these effects and preventing future cardiovascular and metabolic pathology in subsequent generations.

Acetaminophen in late pregnancy and potential for in utero closure of the ductus arteriosus-a pharmacokinetic evaluation and critical review of the literature.

Acetaminophen has become a novel treatment option for patent ductus arteriosus closure in premature infants. This raises concerns about whether acetaminophen should be avoided in late pregnancy, similar to nonsteroidal anti-inflammatory drugs, because of the risk of in utero ductus arteriosus closure. This article critically evaluated the literature reporting an association between acetaminophen use and in utero ductus arteriosus closure and provided a comparative pharmacokinetic analysis of fetal acetaminophen exposure in pregnancy vs drug levels in neonates, with the goal of making an expert recommendation regarding its safety. Here, 1 prospective cohort study and 12 case reports and series evaluating the risk of premature ductus arteriosus closure with prenatal acetaminophen use were reported and overall do not suggest causation. Pharmacokinetic studies showed that acetaminophen fetal transplacental exposures are well below the levels shown to close the ductus arteriosus in neonates. Short-term use of acetaminophen in the third trimester of pregnancy poses a negligible risk of premature ductus arteriosus closure and can still be considered safe in the third trimester of pregnancy at recommended doses.

Adrenal Cushing Syndrome Diagnosed During Pregnancy: Successful Medical Management With Metyrapone.

Adrenal Cushing syndrome during pregnancy is rare, and there is limited information on the effect and safety of metyrapone treatment both for mother and fetus. We present a 24-year-old woman diagnosed with adrenal Cushing syndrome at the end of the second trimester. We elected treatment with metyrapone titrated to 250 mg 3 times daily, resulting in good clinical response and maternal serum and saliva cortisol levels in the upper half of the normal pregnancy range. A healthy male infant was born at 35 weeks' gestation, with no clinical signs of adrenal insufficiency, this despite a low cortisol of 5 nmol/L on the first day of life. We measured metyrapone in maternal and umbilical cord blood samples, demonstrating fetal venous metyrapone levels similar to maternal venous concentration, and a fetal arterial cord concentration at about 60% of the fetal venous cord concentration. This case demonstrates that salivary cortisol levels may be used to monitor the effect of metyrapone on adrenal Cushing syndrome during pregnancy. We show, for the first time in humans, that metyrapone does cross the placenta and may suppress fetal cortisol production without necessarily causing clinical signs of adrenal insufficiency.

Measuring fetal adipose tissue using 3D water-fat magnetic resonance imaging: a feasibility study.

Purpose: Analysis of fetal adipose tissue volumes may provide useful insight towards assessment of overall fetal health, especially in cases with abnormal fetal growth. Here, we assess whether fetal adipose tissue volume can be reliably measured using 3D water-fat MRI, using a quantitative assessment of the lipid content of tissues.Materials and methods: Seventeen women with singleton pregnancies underwent a fetal MRI and water-only and fat-only images were acquired (modified 2-point Dixon technique). Water and fat images were used to generate a fat signal fraction (fat/(water + fat)) from which subcutaneous adipose tissue was segmented along the fetal trunk. Inter-rater (three readers) and intrarater reliability was assessed using intraclass-correlation coefficients (ICC) for 10 image sets. Relationships between adipose tissue measurements and gestational age and estimated fetal weight percentiles were examined.Results: The ICC of the inter-rater reliability was 0.936 (p < .001), and the ICC of the intrarater reliability was 0.992 (p < .001). Strong positive correlations were found between adipose tissue measurements (lipid volume, lipid volume/total fetal volume, mean fat signal fraction) and gestational age.Conclusions: 3D water-fat MRI can reliably measure volume and quantify lipid content of fetal subcutaneous adipose tissues.

IFN-gamma-mediated extravillous trophoblast outgrowth inhibition in first trimester explant culture: a role for insulin-like growth factors.

Pre-eclampsia is often associated with inadequate cytotrophoblast invasion and remodelling of the uterine spiral arteries. Examining a first trimester, 2D in vitro explant culture model which mimics in vivo placentation, including trophoblast column formation and extravillous cytotrophoblast (EVT) migration, we previously suggested that excessive maternal decidual natural killer cell interferon (IFN-gamma) limits EVT migration. Types-1 and -2 insulin-like growth factor (IGF-1, IGF-2) are trophic for EVT, act through their surface receptors, IGFR-1 and IGFR-2, and are regulated by the IGF-binding proteins (IGFBPs). Could the observed IFN-gamma-mediated inhibition of EVT outgrowth and migration be related to either expression changes of IGF-1 or IGF-2, their receptors, their binding proteins, or apoptosis? Using the 2D explant culture model, we examined the effect of IFN-gamma exposure on IGF-1 and -2, IGFR-1 and -2, IGFBPs and apoptosis. IFN-gamma relatively increased IGF-1 and -2 secretion. In EVT, IFN-gamma decreased IGFR-2, but not IGFR-1 expression. IGBP-2, -3 and -4 production were not influenced by IFN-gamma. IFN-gamma induced trophoblast apoptosis measured by the highly sensitive M30 neo-epitope, but not caspase 3 activity, in conditioned medium and EVT cell lysates. The observed IFN-gamma-mediated EVT migration inhibition may occur through the down-regulation of IGFR-2 and subtle induction of EVT apoptosis.

The role of decidual natural killer cells in normal placentation and in the pathogenesis of preeclampsia.

Adequate invasion of the human placenta during the first weeks of pregnancy is a critical step in ensuring both fetal and maternal health. A rapidly expanding body of evidence suggests that decidual natural killer (dNK) cells, a distinct population of CD56brightCD16- lymphocytes, are key regulators of this complex process. Experiments using murine models and in vitro evidence using human tissue cultures suggest that dNK cells modulate extravillous trophoblast (EVT) invasion and remodelling of maternal spiral arteries via both contact-dependent and contact-independent mechanisms. In addition, the differential expression of surface receptors by dNK cells may have a role in determining reproductive success through modulation of the maternal immune system at the time of implantation and placentation. The roles of cytokines, chemokines, and growth factors secreted by dNK cells and their influence on EVT migration, invasion, and pseudovasculogenesis are of particular interest. We reviewed the available experimental evidence related to the functional relationships between dNK cells and trophoblasts at the time of placentation to elucidate potential clinical correlations with human pathologies, including preeclampsia, recurrent pregnancy loss, IVF failure, and placenta accreta.

Preeclampsia biomarkers: An assessment of maternal cardiometabolic health.

Preeclampsia is a serious pregnancy condition defined as new-onset hypertension and proteinuria, commonly characterized as either early, 'placental', or late onset, 'maternal', using a cut-off of 34 weeks gestation. However, it may be more useful to differentiate between the vascular remodelling and placental invasion vs. inflammation and metabolic pathophysiology that underlie these forms of preeclampsia. Due to rising rates of obesity, the late-onset, maternal form is increasingly occurring earlier in pregnancy. Predictive tests for preeclampsia typically include biophysical markers such as maternal body mass index and mean arterial pressure, indicating the importance of cardiovascular and metabolic health in its pathophysiology. In contrast, the placental, inflammatory, endothelial and/or metabolic biomarkers used in these tests are generally thought to indicate an abnormal response to placentation and predict the disease. However, many of these non-placental biomarkers are known to predict impaired metabolic health in non-pregnant subjects with obesity (metabolically unhealthy obesity) and coronary artery disease or stroke in people at risk for cardiovascular events. Similarities between the performance of these markers in the prediction of cardiovascular and metabolic health outside of pregnancy suggests that they may be more indicative of maternal health than predictive for preeclampsia. This paper reviews the biophysical and biochemical markers in preeclampsia prediction and compares their performance to tests assessing metabolic health and risk of cardiovascular disease, particularly in the obese population.

Altered maternal and placental lipid metabolism and fetal fat development in obesity: Current knowledge and advances in non-invasive assessment.

Abnormal maternal lipid profiles, a hallmark of increased maternal adiposity, are associated with pregnancy complications such as preeclampsia and gestational diabetes, and offspring long-term metabolic health is impacted as the consequence of altered fetal growth, physiology and often iatrogenic prematurity. The metabolic changes associated with maternal obesity and/or the consumption of a high-fat diet effecting maternal lipid profiles and metabolism have also been documented to specifically affect placental function and may underlie changes in fetal development and life course disease risk. The placenta plays a critical role in mediating nutritional signals between the fetus and the mother. As obesity rates in women of reproductive age continue to increase, it is becoming evident that inclusion of new technologies that allow for a better understanding of early changes in placental lipid transport and metabolism, non-invasively in maternal circulation, maternal tissues, placenta, fetal circulation and fetal tissues are needed to aid timely clinical diagnosis and treatment for obesity-associated diseases. This review describes pregnancy lipid homeostasis, with specific reference to changes arising from altered maternal body composition on placental and fetal lipid transport and metabolism. Current technologies for lipid assessments, such as metabolomics and lipidomics may be impacted by labour or mode of delivery and are only reflective of a single time point. This review further addresses how established and novel technologies for assessing lipids and their metabolism non-invasively and during the course of pregnancy may guide future research into the effect of maternal metabolic health on pregnancy outcome, placenta and fetus.