Predictive and Diagnostic Value of the Angiogenic Proteins in Patients With Chronic Kidney Disease.

BACKGROUND: Our objective was to investigate the predictive and diagnostic accuracy of the angiogenic proteins sFlt-1 (soluble fms-like tyrosine kinase-1) and PlGF (placental growth factor) for preterm preeclampsia and explore the relationship between renal function and these proteins. METHODS: We completed a blinded, prospective, longitudinal, observational study of patients with chronic kidney disease followed at a tertiary center (2018-2023). Serum samples were obtained at 3 time points along gestation (planned sampling): 12-16, 18-22, and 28-32 weeks. In addition, samples were obtained whenever preeclampsia was suspected (indicated sampling). sFlt-1 and PlGF levels remained concealed until the study ended. The primary outcome was preterm preeclampsia. The planned and indicated samples were used to estimate the predictive and diagnostic accuracy of the angiogenic proteins, respectively. RESULTS: Of the 97 participants, 21 (21.6%) experienced preterm preeclampsia. In asymptomatic patients with chronic kidney disease, the angiogenic proteins were predictive of preterm preeclampsia only when sampled in the third trimester, in which case the sFlt-1/PlGF ratio (false positive rate of 37% for a detection rate of 80%) was more predictive than either sFlt-1 or PlGF in isolation. In patients with suspected preeclampsia, the diagnostic accuracy of the sFlt-1/PlGF ratio (false positive rate of 26% for a detection rate of 80%) was higher than that of sFlt-1 and PlGF in isolation. Diminished renal function was associated with increased levels of PlGF. CONCLUSIONS: sFlt-1 and PlGF can effectively predict and improve the diagnostic accuracy for preterm preeclampsia among patients with chronic kidney disease. The optimal sFlt-1/PlGF ratio cutoff to rule out preeclampsia may need to be lower in patients with impaired renal function.

Maternal Placental Growth Factor (PlGF) levels, sonographic placental parameters, and outcomes of IVF pregnancies with and without embryo trophectoderm biopsy.

PURPOSE: In vitro fertilization (IVF) is associated with abnormal trophoblast invasion and resultant decreased levels of circulating placental biomarkers such as placental growth factor (PlGF). Our objective was to evaluate maternal serum levels of second/third trimester PlGF, sonographic placental parameters, and clinical outcomes among IVF frozen embryo transfer (FET) pregnancies with and without embryo trophectoderm biopsy. METHODS: This was a retrospective study of pregnant patients who conceived using a single frozen embryo transfer (FET) and gave birth between 30 January 2018 and 31 May 2021. We compared PlGF levels, sonographic placental parameters, and clinical outcomes between FET with biopsy and FET without biopsy groups. RESULTS: The median PlGF level was 614.5 pg/mL (IQR 406-1020) for FET pregnancies with biopsy, and 717.0 pg/mL (IQR 552-1215) for FET pregnancies without biopsy. The adjusted mean difference was 190.9 pg/mL lower in the FET biopsy group (95% CI, -410.6, 28.8; p = 0.088). There were no statistically significant differences in placental parameters or clinical pregnancy outcomes. CONCLUSION: This exploratory study demonstrated a possible trend toward lower maternal serum PlGF in the pregnancies conceived with FET using a biopsied embryo. Further investigation is warranted into the potential placental health effects of trophectoderm biopsy.

Phenotypes of maternal vascular malperfusion placental pathology and adverse pregnancy outcomes: A retrospective cohort study.

OBJECTIVE: To identify which components of maternal vascular malperfusion (MVM) pathology are associated with adverse pregnancy outcomes and to investigate the morphological phenotypes of MVM placental pathology and their relationship with distinct clinical presentations of pre-eclampsia and/or fetal growth restriction (FGR). DESIGN: Retrospective cohort study. SETTING: Tertiary care hospital in Toronto, Canada. POPULATION: Pregnant individuals with low circulating maternal placental growth factor (PlGF) levels (<100 pg/mL) and placental pathology analysis between March 2017 and December 2019. METHODS: Association between each pathological finding and the outcomes of interest were calculated using the chi-square test. Cluster analysis and logistic regression was used to identify phenotypic clusters, and their association with adverse pregnancy outcomes. Cluster analysis was performed using the K-modes unsupervised clustering algorithm. MAIN OUTCOME MEASURES: Preterm delivery <34+0 weeks of gestation, early onset pre-eclampsia with delivery <34+0 weeks of gestation, birthweight <10th percentile (small for gestational age, SGA) and stillbirth. RESULTS: The diagnostic features of MVM most strongly associated with delivery <34+0 weeks of gestation were: infarction, accelerated villous maturation, distal villous hypoplasia and decidual vasculopathy. Two dominant phenotypic clusters of MVM pathology were identified. The largest cluster (n = 104) was characterised by both reduced placental mass and hypoxic ischaemic injury (infarction and accelerated villous maturation), and was associated with combined pre-eclampsia and SGA. The second dominant cluster (n = 59) was characterised by infarction and accelerated villous maturation alone, and was associated with pre-eclampsia and average birthweight for gestational age. CONCLUSIONS: Patients with placental MVM disease are at high risk of pre-eclampsia and FGR, and distinct pathological findings correlate with different clinical phenotypes, suggestive of distinct subtypes of MVM disease.

Fetal Hemodynamics, Early Survival, and Neurodevelopment in Patients With Cyanotic Congenital Heart Disease.

BACKGROUND: Fetuses with cyanotic congenital heart disease (CHD) exhibit profound fetal circulatory disturbances that may affect early outcomes. OBJECTIVES: This study sought to investigate the relationship between fetal hemodynamics and early survival and neurodevelopmental (ND) outcomes in patients with cyanotic CHD. METHODS: In this longitudinal observational study, fetuses with cyanotic CHD underwent late gestational fetal cardiovascular magnetic resonance (CMR) to measure vessel blood flow and oxygen content. Superior vena cava (SVC) flow was used as a proxy for cerebral blood flow. Primary outcomes were 18-month mortality and Bayley Scales of Infant Development-III assessment. RESULTS: A total of 144 fetuses with cyanotic CHD were assessed. By 18 months, 18 patients (12.5%) died. Early mortality was associated with reduced combined ventricular output (P = 0.01), descending aortic flow (P = 0.04), and umbilical vein flow (P = 0.03). Of the surviving patients, 71 had ND outcomes assessed. Cerebral oxygen delivery was the fetal hemodynamic variable most strongly associated with cognitive, language, and motor outcomes (P < 0.05). Fetal SVC flow was also associated with cognitive, language, and motor outcomes (P < 0.01), and it remained an independent predictor of cognitive (P = 0.002) and language (P = 0.04) outcomes after adjusting for diagnosis. Diminished SVC flow also performed better than other fetal CMR and echocardiographic predictors of cognitive ND delay (receiver-operating characteristic curve area: 0.85; SE 0.05). CONCLUSIONS: Among fetuses with cyanotic CHD, diminished fetal combined ventricular output is associated with mortality, whereas cerebral blood flow and oxygen delivery are associated with early cognitive, language, and motor development at 18 months of age. These results support the inclusion of fetal CMR to help identify patients at risk of adverse ND outcomes.

Maternal exposure to polyethylene micro- and nanoplastics impairs umbilical blood flow but not fetal growth in pregnant mice.

While microplastics have been recently detected in human blood and the placenta, their impact on human health is not well understood. Using a mouse model of environmental exposure during pregnancy, our group has previously reported that exposure to polystyrene micro- and nanoplastics throughout gestation results in fetal growth restriction. While polystyrene is environmentally relevant, polyethylene is the most widely produced plastic and amongst the most commonly detected microplastic in drinking water and human blood. In this study, we investigated the effect of maternal exposure to polyethylene micro- and nanoplastics on fetal growth and placental function. Healthy, pregnant CD-1 dams were divided into three groups: 106 ng/L of 740-4990 nm polyethylene with surfactant in drinking water (n = 12), surfactant alone in drinking water (n = 12) or regular filtered drinking water (n = 11). At embryonic day 17.5, high-frequency ultrasound was used to investigate the placental and fetal hemodynamic responses following exposure. While maternal exposure to polyethylene did not impact fetal growth, there was a significant effect on placental function with a 43% increase in umbilical artery blood flow in the polyethylene group compared to controls (p < 0.01). These results suggest polyethylene has the potential to cause adverse pregnancy outcomes through abnormal placental function.

Polystyrene micro- and nanoplastics cause placental dysfunction in mice†.

Maternal exposure to microplastics and nanoplastics has been shown to result in fetal growth restriction in mice. In this study, we investigated the placental and fetal hemodynamic responses to plastics exposure in mice using high-frequency ultrasound. Healthy, pregnant CD-1 dams were given either 106 ng/L of 5 µm polystyrene microplastics or 106 ng/L of 50 nm polystyrene nanoplastics in drinking water throughout gestation and were compared with controls. Maternal exposure to both microplastics and nanoplastics resulted in evidence of placental dysfunction that was highly dependent on the particle size. The umbilical artery blood flow increased by 48% in the microplastic-exposed group and decreased by 25% in the nanoplastic-exposed group compared to controls (p < 0.05). The microplastic- and nanoplastic-exposed fetuses showed a significant decrease in the middle cerebral artery pulsatility index of 10% and 13%, respectively, compared to controls (p < 0.05), indicating vasodilation of the cerebral circulation, a fetal adaptation that is part of the brain sparing response to preserve oxygen delivery. Hemodynamic markers of placental dysfunction and fetal hypoxia were more pronounced in the group exposed to polystyrene nanoplastics, suggesting nanoplastic exposure during human pregnancy has the potential to disrupt fetal brain development, which in turn may cause suboptimal neurodevelopmental outcomes.

Delivery outcomes in the subsequent pregnancy following the conservative management of placenta accreta spectrum disorder: a systematic review and meta-analysis.

OBJECTIVE: Cesarean hysterectomy is generally presumed to decrease maternal morbidity and mortality secondary to placenta accreta spectrum disorder. Recently, uterine-sparing techniques have been introduced in conservative management of placenta accreta spectrum disorder to preserve fertility and potentially reduce surgical complications. However, despite patients often expressing the intention for future conception, few data are available regarding the subsequent pregnancy outcomes after conservative management of placenta accreta spectrum disorder. Thus, we aimed to perform a systematic review and meta-analysis to assess these outcomes. DATA SOURCES: PubMed, Scopus, and Web of Science databases were searched from inception to September 2022. STUDY ELIGIBILITY CRITERIA: We included all studies, with the exception of case studies, that reported the first subsequent pregnancy outcomes in individuals with a history of placenta accreta spectrum disorder who underwent any type of conservative management. METHODS: The R programming language with the "meta" package was used. The random-effects model and inverse variance method were used to pool the proportion of pregnancy outcomes. RESULTS: We identified 5 studies involving 1458 participants that were eligible for quantitative synthesis. The type of conservative management included placenta left in situ (n=1) and resection surgery (n=1), and was not reported in 3 studies. The rate of placenta accreta spectrum disorder recurrence in the subsequent pregnancy was 11.8% (95% confidence interval, 1.1-60.3; I2=86.4%), and 1.9% (95% confidence interval, 0.0-34.1; I2=82.4%) of participants underwent cesarean hysterectomy. Postpartum hemorrhage occurred in 10.3% (95% confidence interval, 0.3-81.4; I2=96.7%). A composite adverse maternal outcome was reported in 22.7% of participants (95% confidence interval, 0.0-99.4; I2=56.3%). CONCLUSION: Favorable pregnancy outcome is possible following successful conservation of the uterus in a placenta accreta spectrum disorder pregnancy. Approximately 1 out of 4 subsequent pregnancies following conservative management of placenta accreta spectrum disorder had considerable adverse maternal outcomes. Given such high incidence of adverse outcomes and morbidity, patient and provider preparation is vital when managing this population.

Maternal exposure to polystyrene nanoplastics alters fetal brain metabolism in mice.

INTRODUCTION: Plastics used in everyday materials accumulate as waste in the environment and degrade over time. The impacts of the resulting particulate micro- and nanoplastics on human health remain largely unknown. In pregnant mice, we recently demonstrated that exposure to nanoplastics throughout gestation and during lactation resulted in changes in brain structure detected on MRI. One possible explanation for this abnormal postnatal brain development is altered fetal brain metabolism. OBJECTIVES: To determine the effect of maternal exposure to nanoplastics on fetal brain metabolism. METHODS: Healthy pregnant CD-1 mice were exposed to 50 nm polystyrene nanoplastics at a concentration of 106 ng/L through drinking water during gestation. Fetal brain samples were collected at embryonic day 17.5 (n = 18-21 per group per sex) and snap-frozen in liquid nitrogen. Magic angle spinning nuclear magnetic resonance was used to determine metabolite profiles and their relative concentrations in the fetal brain. RESULTS: The relative concentrations of gamma-aminobutyric acid (GABA), creatine and glucose were found to decrease by 40%, 21% and 30% respectively following maternal nanoplastic exposure when compared to the controls (p < 0.05). The change in relative concentration of asparagine with nanoplastic exposure was dependent on fetal sex (p < 0.005). CONCLUSION: Maternal exposure to polystyrene nanoplastics caused abnormal fetal brain metabolism in mice. The present study demonstrates the potential impacts of nanoplastic exposure during fetal development and motivates further studies to evaluate the risk to human pregnancies.

Feasibility of MRI assessment of maternal-fetal oxygen transport and consumption relative to maternal position in healthy late gestational pregnancies.

Late gestational supine positioning reduces maternal cardiac output due to inferior vena caval (IVC) compression, despite increased collateral venous return. However, little is known about the impact of maternal position on oxygen (O2 ) delivery and consumption of the gravid uterus, fetus, placenta and lower limbs. We studied the effects of maternal positioning on these parameters in 20 healthy pregnant subjects at 36 ± 2 weeks using magnetic resonance imaging (MRI); a follow-up MRI was performed 6-months postpartum (n = 16/20). MRI techniques included phase-contrast and T1/T2 relaxometry for blood flow and oximetry imaging, respectively. O2 transport was measured in the following vessels (bilateral where appropriate): maternal abdominal descending aorta (DAoabdo ), IVC, ovarian, paraspinal veins (PSV), uterine artery (UtA) and external iliacs, and umbilical. Maternal cardiac output was measured by summing DAothoracic and superior vena cava flows. Supine mothers (n = 6) had lower cardiac output and O2 delivery in the DAoabdo , UtA and external iliac arteries, and higher PSV flow than those in either the left (n = 8) or right (n = 6) lateral positions during MRI. However, O2 consumption in the gravid uterus, fetus, placenta and lower limbs was unaffected by maternal positioning. The ratio of IVC/PSV flow decreased in supine mothers while ovarian venous flow and O2 saturation were unaltered, suggesting a major route of pelvic venous return unaffected by maternal position. Placental-fetal O2 transport and consumption were similar between left and right lateral maternal positions. In comparison to non-pregnant findings, DAoabdo and UtA O2 delivery and pelvic O2 consumption increased, while lower-limb consumption remained constant , despite reduced external iliac artery O2 delivery in late gestation. KEY POINTS: Though sleeping supine during the third trimester is associated with an increased risk of antepartum stillbirth, the underlying biological mechanisms are not fully understood. Maternal cardiac output and uteroplacental flow are reduced in supine mothers due to inferior vena caval compression from the weight of the gravid uterus. This MRI study provides a comprehensive circulatory assessment, demonstrating reduced maternal cardiac output and O2 delivery (uteroplacental, lower body) in supine compared to lateral positioning; however, O2 consumption (gravid uterus, fetus, placenta, lower limbs) was preserved. Unlike other mammalian species, the ovarian veins conduct substantial venous return from the human pregnant uterus that is unaffected by maternal positioning. Lumbar paraspinal venous flow increased in supine mothers. These observations may have important considerations during major pelvic surgery in pregnancy (i.e. placenta percreta). Future studies should address the importance of maternal positioning as a potential tool to deliver improved perinatal outcomes in pregnancies with compromised uteroplacental O2 delivery.

Rosiglitazone-Mediated Activation of PPARγ Restores HO1 Expression in the Human Preeclamptic Placenta.

BACKGROUND: Preeclampsia is a hypertensive disorder of pregnancy characterized by chronic placental ischemia and suppression of proangiogenic proteins, causing oxidative stress, hypertension, and maternal systemic organ damage. The transcription factor, PPARγ (peroxisome proliferator-activated receptor-γ) promotes healthy trophoblast differentiation but is dysregulated in the preeclampsia placenta. Our study identifies the beneficial impact of Rosiglitazone-mediated PPARγ-activation in the stressed preeclampsia placenta. METHODS: We used first trimester placentas, preeclamptic and preterm control placentas, and human trophoblast cell lines to study PPARγ activation. RESULTS: Induction of PPARγ activates cell growth and antioxidative stress pathways, including the gene, heme oxygenase 1 (Hmox1). Protein expression of both PPARγ and HO1 (heme oxygenase 1) are reduced in preeclamptic placentas, but Rosiglitazone restores HO1 signaling in a PPARγ-dependent manner. CONCLUSIONS: Restoring disrupted pathways by PPARγ in preeclampsia offers a potential therapeutic pathway to reverse placental damage, extending pregnancy duration, and reduce maternal sequelae. Future research should aim to understand the full scope of impaired PPARγ signaling in the human placenta and focus on compounds for safe use during pregnancy to prevent severe perinatal morbidity and mortality.

Inpatient vs outpatient management of pregnancies with vasa previa: A historical cohort study.

INTRODUCTION: Vasa previa, a condition where unprotected fetal blood vessels lie in proximity to the internal cervical opening, is a potentially lethal obstetric complication. The precarious situation of these vessels increases the risk of fetal hemorrhage with spontaneous or artificial rupture of membranes, frequently causing fetal/neonatal demise or severe morbidity. As a result, in many centers, inpatient management forms the mainstay when vasa previa is diagnosed antenatally. This study aimed to determine whether a subpopulation of pregnancies diagnosed antenatally with vasa previa could be safely managed as outpatients. MATERIAL AND METHODS: We reviewed all cases of vasa previa in singleton pregnancies, with no fetal anomalies, diagnosed at Mount Sinai Hospital, Toronto, from January 2008 to December 2017. Cases were categorized into three arms for analysis: outpatients (OP), asymptomatic hospitalized (ASH) and symptomatic hospitalized (SH). The SH arm included patients admitted with any antepartum bleeding or suspicious fetal non-stress test. Those that presented with symptomatic uterine activity/threatened preterm labor and delivered within 7 days of diagnosis were excluded from the study. Records were analyzed for details on hospitalization, antenatal corticosteroid administration, cervical length measurements, and fetal/neonatal mortality and morbidity. RESULTS: Of the 84 antenatally-diagnosed cases of vasa previa, 47 fulfilled eligibility criteria. A total of 15 cases were managed as OP, 22 as ASH and 10 as SH. Unplanned cesareans were highest in the SH arm (40% vs. 0% ASH vs. 13.3% OP). Those in the SH arm delivered earliest (median 33.8 weeks, interquartile range (IQR) 33.2-34.3 weeks). Of the asymptomatic patients, those in the ASH arm delivered earlier than those in the OP arm (35.3 [34.6-36.2] weeks vs. 36.7 [35.6-37.2] weeks, p = 0.037). There were no cases of fetal/neonatal death, anemia or severe neonatal morbidity and no significant differences between groups based on cervical length or antenatal corticosteroid administration. CONCLUSIONS: Our study suggests that asymptomatic women with an antenatal diagnosis of vasa previa, singleton pregnancies, and at low risk for preterm birth may safely managed as outpatients, as long as they are able to access hospital promptly in the event of antepartum bleeding or early labor.

Indications and Outcomes for Planned Cesarean Hysterectomy in Non-Placenta Accreta Spectrum Disorder Patients: A Systematic Review.

OBJECTIVE: Planned hysterectomy at the time of cesarean delivery may be reasonable in cases other than placenta accreta spectrum disorders. Our objective was to synthesize the published literature on the indications and outcomes for planned cesarean hysterectomy. DATA SOURCES: We performed a systematic review of published literature from the following databases from inception (1946) to June 2021: MEDLINE, PubMed, EMBASE, Cochrane CENTRAL, DARE, and clinicaltrials.gov. STUDY SELECTION: We included all study designs where subjects underwent planned cesarean delivery with simultaneous hysterectomy. Emergency procedures and those performed for placenta accreta spectrum disorders were excluded. DATA EXTRACTION AND SYNTHESIS: The primary outcome was surgical indication, though other surgical outcomes were evaluated when data permitted. Quantitative analysis was limited to studies published in 1990 or later. Risk of bias was assessed using an adaptation of the ROBINS-I tool. CONCLUSION: The most common indication for planned cesarean hysterectomy was malignancy, with cervical cancer being the most frequent. Other indications included permanent contraception, uterine fibroids, menstrual disorders, and chronic pelvic pain. Common complications included bleeding, infection, and ileus. The surgical skill for cesarean hysterectomy continues to be relevant in contemporary obstetrical practice for reproductive malignancy and several benign indications. Although the data indicate relatively safe outcomes, these studies show significant publication bias and, therefore, further systematic study of this procedure is justified. PROSPERO REGISTRATION NUMBER: CRD42021260545, registered June 16, 2021.

Placenta Accreta Spectrum Disorders: A National Survey.

OBJECTIVES: Describe the current practice of Canadian obstetricians-gynaecologists in managing placenta accreta spectrum (PAS) disorders from suspicion of diagnosis to delivery planning and explore the impact of the latest national practice guidelines on this topic. METHODS: We distributed a cross-sectional bilingual electronic survey to Canadian obstetricians-gynaecologists in March-April 2021. Demographic data and information on screening, diagnosis, and management were collected using a 39-item questionnaire. The survey was validated and pretested among a sample population. Descriptive statistics were used to present the results. RESULTS: We received 142 responses. Almost 60% of respondents said they had read the latest Society of Obstetricians and Gynaecologists of Canada clinical practice guideline on PAS disorders, published in July 2019. Nearly 1 in 3 respondents changed their practice following this guideline. Respondents highlighted the importance of 4 key points: (1) limiting travel to thereby remain close to a regional care centre, (2) preoperative anemia optimization, (3) performance of cesarean-hysterectomy leaving the placenta in situ (83%), (4) access via midline laparotomy (65%). Most respondents recognized the importance of perioperative blood loss reduction strategies such as tranexamic acid and perioperative thromboprophylaxis via sequential compression devices and low-molecular-weight heparin until full mobilization. CONCLUSIONS: This study demonstrates the impact of the Society of Obstetricians and Gynaecologists of Canada's PAS clinical practice guideline on management choices made by Canadian clinicians. Our study highlights the value of a multidisciplinary approach to reducing maternal morbidity in individuals facing surgery for a PAS disorder and the importance of regionalized care that is resourced to provide maternal-fetal medicine and surgical expertise, transfusion medicine, and critical care support.

Engaging pregnant individuals and healthcare professionals in an international mixed methods study to develop a core outcome set for studies on placenta accreta spectrum disorder (COPAS): a study protocol.

INTRODUCTION: Placenta accreta spectrum (PAS) disorder is a life-threatening condition that may result in serious maternal complications, including mortality. The placenta which is pathologically adherent to the uterine wall, places individuals at high risk of major haemorrhage during the third stage of labour. Current research reports on PAS disorder outcomes have highly variable levels of information, which is therefore difficult for investigators to aggregate to inform practice. There is an urgent need to harmonise data collection in prospective studies to identify and implement best practices for management. One approach to standardise outcomes across any health area via the use of core outcome sets (COSs), which are consensus-derived standardised sets of outcomes that all studies for a particular condition should measure and report. This protocol outlines the steps for developing a COS for PAS disorder (COPAS). METHODS AND ANALYSIS: This protocol outlines steps for the creation of COPAS. The first step, a systematic review, will identify all reported outcomes in the scientific literature. The second step will use qualitative one-on-one interviews to identify additional outcomes identified as important by patients and healthcare professionals that are not reported in the published literature. Outcomes from the first two steps will be combined to form an outcome inventory. This outcome inventory will inform the third step which is a Delphi survey that encourages agreement between patients and healthcare professionals on which outcomes are most important for inclusion in the COS. The fourth step, a consensus group meeting of representative participants, will finalise outcomes for inclusion in the PAS disorder COS. ETHICS AND DISSEMINATION: This study has obtained Research Ethics Board approval from Sunnybrook Health Sciences Centre (#2338, #1488). We will aim to publish the study findings in an international peer-reviewed OBGYN journal. REGISTRATION DETAILS: COMET Core Outcome Set Registration: https://www.comet-initiative.org/Studies/Details/1127. PROSPERO REGISTRATION NUMBER: CRD42020173426.