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.

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.

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.

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.

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.

Comparison of circulating maternal placenta growth factor levels and sonographic evaluation of patients with abnormal first trimester screening analytes.

OBJECTIVE: To evaluate the role of mid-trimester placental growth factor (PlGF) in patients with abnormal circulating levels of first-trimester biomarkers. METHODS: Retrospective cohort study including singleton pregnancies complicated by abnormal first-trimester biomarkers (2017-2020). Pregnancies complicated with chromosomal/structural anomalies were excluded. All patients had ultrasound imaging including uterine artery Doppler combined with measurement of maternal circulating PlGF. Sonographic findings, maternal and perinatal outcomes, and placental histopathology were compared between pregnancies with normal and low (<10th percentile for gestational age) PlGF levels. The diagnostic accuracy of PlGF for the prediction of specific placental-mediated complications was compared with the uterine artery Doppler assessment and additional sonographic findings. RESULTS: Seventy-one pregnancies were assessed, of which 35 (49.3%) had low PlGF levels. Maternal sociodemographic characteristics, nulliparity, and aspirin consumption were comparable. In comparison with patients with normal PlGF levels, individuals with low PlGF levels had a higher rate of fetal growth restriction (EFW <3rd centile; 42.9% vs. 8.3%, p = 0.001), preterm-preeclampsia (22.9% vs. 0%, p = 0.002), preterm delivery <34 weeks (54.3% vs. 8.3%, p < 0.001) and maternal vascular malperfusion placental pathology (72.7% vs. 21.7%, p < 0.001) following delivery. Adjusting for uterine artery Doppler and fetal biometry status, mid-trimester low PlGF remained significantly associated with these placental-mediated complications. The predictive capacity of PlGF outperformed ultrasound imaging with only minimal diagnostic improvement when ultrasound information was combined with PlGF status. CONCLUSION: In pregnancies with unexplained abnormal first-trimester biomarkers, mid-trimester PlGF outperformed a comprehensive ultrasound assessment in the identification of a subset of patients destined to develop placental dysfunction. This blood test may be an alternative initial approach in this context, especially where access to specialist care is more geographically challenging.

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.

Maternal exposure to polystyrene microplastics alters placental metabolism in mice.

INTRODUCTION: The rapid growth in the worldwide use of plastics has resulted in a vast accumulation of microplastics in the air, soil and water. The impact of these microplastics on pregnancy and fetal development remains largely unknown. In pregnant mice, we recently demonstrated that exposure to micro- and nanoplastics throughout gestation resulted in significant fetal growth restriction. One possible explanation for reduced fetal growth is abnormal placental metabolism. OBJECTIVES: To evaluate the effect of maternal exposure to microplastics on placental metabolism. METHODS: In the present study, CD-1 pregnant mice were exposed to 5 µm polystyrene microplastics in filtered drinking water at one of four concentrations (0 ng/L (controls), 102 ng/L, 104 ng/L, 106 ng/L) throughout gestation (n = 7-11/group). At embryonic day 17.5, placental tissue samples were collected (n = 28-44/group). Metabolite profiles were determined using 1 H high-resolution magic angle spinning magnetic resonance spectroscopy. RESULTS: The relative concentration of lysine (p = 0.003) and glucose (p < 0.0001) in the placenta were found to decrease with increasing microplastic concentrations, with a significant reduction at the highest exposure concentration. Multivariate analysis identified shifts in the metabolic profile with MP exposure and pathway analysis identified perturbations in the biotin metabolism, lysine degradation, and glycolysis/gluconeogenesis pathways. CONCLUSION: Maternal exposure to microplastics resulted in significant alterations in placental metabolism. This study highlights the potential impact of microplastic exposure on pregnancy outcomes and that efforts should be made to minimize exposure to plastics, particularly during pregnancy.

Diagnostic utility of serial circulating placental growth factor levels and uterine artery Doppler waveforms in diagnosing underlying placental diseases in pregnancies at high risk of placental dysfunction.

BACKGROUND: Placental pathology assessment following delivery in pregnancies complicated by preeclampsia, fetal growth restriction, abruption, and stillbirth reveals a range of underlying diseases. The most common pathology is maternal vascular malperfusion, characterized by high-resistance uterine artery Doppler waveforms and abnormal expression of circulating maternal angiogenic growth factors. Rare placental diseases (massive perivillous fibrinoid deposition and chronic histiocytic intervillositis) are reported to have high recurrence risks, but their associations with uterine artery Doppler waveforms and angiogenic growth factors are presently ill-defined. OBJECTIVE: To characterize the patterns of serial placental growth factor measurements and uterine artery Doppler waveform assessments in pregnancies that develop specific types of placental pathology to gain insight into their relationships with the timing of disease onset and pregnancy outcomes. STUDY DESIGN: A retrospective cohort study conducted between January 2017 and November 2021 included all singleton pregnancies with at least 1 measurement of maternal circulating placental growth factor between 16 and 36 weeks' gestation, delivery at our institution, and placental pathology analysis demonstrating diagnostic features of maternal vascular malperfusion, fetal vascular malperfusion, villitis of unknown etiology, chronic histiocytic intervillositis, or massive perivillous fibrinoid deposition. Profiles of circulating placental growth factor as gestational age advanced were compared between these placental pathologies. Maternal and perinatal outcomes were recorded. RESULTS: A total of 337 pregnancies from 329 individuals met our inclusion criteria. These comprised placental pathology diagnoses of maternal vascular malperfusion (n=109), fetal vascular malperfusion (n=87), villitis of unknown etiology (n=96), chronic histiocytic intervillositis (n=16), and massive perivillous fibrinoid deposition (n=29). Among patients who developed maternal vascular malperfusion, placental growth factor levels gradually declined as pregnancy progressed (placental growth factor <10th percentile at 16-20 weeks' gestation in 42.9%; 20-24 weeks in 61.9%; 24-28 weeks in 77%; and 28-32 weeks in 81.4%) accompanied by mean uterine artery Doppler pulsatility index >95th percentile in 71.6% cases. Patients who developed either fetal vascular malperfusion or villitis of unknown etiology mostly exhibited normal circulating placental growth factor values in association with normal uterine artery Doppler waveforms (mean [standard deviation] pulsatility index values: fetal vascular malperfusion, 1.14 [0.49]; villitis of unknown etiology, 1.13 [0.45]). Patients who developed either chronic histiocytic intervillositis or massive perivillous fibrinoid deposition exhibited persistently low placental growth factor levels from the early second trimester (placental growth factor <10th centile at 16-20 weeks' gestation in 80% and 77.8%, respectively; 20-24 weeks in 88.9% and 63.6%; 24-28 weeks in 85.7% and 75%), all in combination with normal uterine artery Doppler waveforms (mean pulsatility index >95th centile: chronic histiocytic intervillositis, 25%; massive perivillous fibrinoid deposition, 37.9%). Preeclampsia developed in 83 of 337 (24.6%) patients and was most common in those developing maternal vascular malperfusion (54/109, 49.5%) followed by chronic histiocytic intervillositis (7/16, 43.8%). There were 29 stillbirths in the cohort (maternal vascular malperfusion, n=10 [9.2%]; fetal vascular malperfusion, n=5 [5.7%]; villitis of unknown etiology, n=1 [1.0%]; chronic histiocytic intervillositis, n=7 [43.8%]; massive perivillous fibrinoid deposition, n=6 [20.7%]). Most patients experiencing stillbirth exhibited normal uterine artery Doppler waveforms (21/29, 72.4%) and had nonmaternal vascular malperfusion pathologies (19/29, 65.5%). By contrast, 28 of 29 (96.5%) patients experiencing stillbirth had ≥1 low placental growth factor values before fetal death. CONCLUSION: Serial circulating maternal placental growth factor tests, in combination with uterine artery Doppler waveform assessments in the second trimester, may indicate the likely underlying type of placental pathology mediating severe adverse perinatal events. This approach has the potential to test disease-specific therapeutic strategies to improve clinical outcomes. Serial placental growth factor testing, compared with uterine artery Doppler studies, identifies a greater proportion of patients destined to have a poor perinatal outcome because diseases other than maternal vascular malperfusion are characterized by normal uteroplacental circulation.

Circulating maternal placental growth factor responses to low-molecular-weight heparin in pregnant patients at risk of placental dysfunction.

BACKGROUND: Patients at high risk of severe preeclampsia and fetal growth restriction have low circulating levels of placental growth factor and features of maternal vascular malperfusion placental pathology at delivery. Multimodal screening and commencement of aspirin prophylaxis at 11 to 13 weeks' gestation markedly reduces the risk of preterm delivery with preeclampsia. However, the additional role of low-molecular-weight heparin and mechanisms of action remain uncertain. Because low-molecular-weight heparin augments the production and release of placental growth factor in vitro by both placental villi and vascular endothelium, it may be effective to suppress the risk of severe preeclampsia in a niche group of high-risk patients with low circulating placental growth factor in the early second trimester. OBJECTIVE: This study aimed to define a gestational age-specific reference range for placental growth factor and to test the hypothesis that prophylactic low-molecular-weight heparin administered in the early second trimester may restore deficient circulating placental growth factor levels and thereby prolong pregnancy. STUDY DESIGN: Centile curves for circulating placental growth factor levels from 12 to 36 weeks' gestation were derived using quantile regression of combined data from a published cohort of 4207 unselected nulliparous patients in Cambridge, United Kingdom, at 4 sampling time points (12, 20, 28, and 36 weeks' gestation) and the White majority (n=531) of a healthy nulliparous cohort in Toronto, Canada, at 16 weeks' gestation using the same test platform. Within a specialty high-risk clinic in Toronto, a niche group of 7 patients with a circulating placental growth factor at the <10th centile in the early second trimester received daily prophylactic low-molecular-weight heparin (enoxaparin; 40 mg subcutaneously) and were followed up until delivery (group 1). Their baseline characteristics, delivery details, and placental pathologies were compared with 5 similar patients who did not receive low-molecular-weight heparin during the observation period (group 2) and further with 21 patients who delivered with severe preeclampsia (group 3) in the same institution. RESULTS: A gestational age-specific reference range for placental growth factor levels at weekly intervals between 12 and 36 weeks was established for White women with singleton pregnancies. Within group 1, 5 of 7 patients demonstrated a sustained increase in circulating placental growth factor levels, whereas placental growth factor levels did not increase in group 2 or group 3 patients who did not receive low-molecular-weight heparin. Group 1 patients receiving low-molecular-weight heparin therapy exhibited a later gestation at delivery, relative to groups 2 and 3 (36 weeks [33-37] vs 23 weeks [22-26] and 28 weeks [27-31], respectively), and consequently had higher birthweights (1.93 kg [1.1-2.7] vs 0.32 kg [0.19-0.39] and 0.73 kg [0.52-1.03], respectively). The incidence of stillbirth was lowest in group 1 (14% [1 of 7]), relative to groups 2 and 3 (80% [4 of 5] and 29% [6 of 21], respectively). Maternal vascular malperfusion was the most common placental pathology found in association with abnormal uterine artery Doppler. CONCLUSION: In patients at high risk of a serious adverse pregnancy outcome owing to placental disease, the addition of low-molecular-weight heparin to aspirin prophylaxis in the early second trimester may restore deficient circulating placental growth factor to mediate an improved perinatal outcome. These data support the implementation of a multicenter pilot randomized control trial where patients are recruited primarily based on the assessment of placental function in the early second trimester.

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.

Improving Early Pregnancy Screening for Placenta Accreta Spectrum: Retrospective Analysis of Early Screening Candidates by Risk Assessment in Canada.

Early screening for placenta accreta spectrum (PAS) is not established in Canada, yet has been demonstrated with a 2-stage strategy in patients classified as at risk at the nuchal translucency examination. We performed a retrospective analysis of women with singleton pregnancies who had first-trimester screening and subsequently had a pathology-confirmed PAS. We sought those who met high-risk clinical criteria for PAS: previous uterine surgeries and an anterior low-lying placenta. Over 80% of women met both high-risk criteria at the nuchal translucency examination. Lack of early recognition and risk stratification resulted in a late median gestational age at suspicion and diagnosis of PAS.

Doppler Ultrasound of the Fetal Descending Aorta: An Objective Tool to Assess Placental Blood Flow Resistance in Pregnancies With Discordant Umbilical Arteries.

OBJECTIVES: To determine the relationship between blood flow in the fetal descending aorta and discordant umbilical arteries (UAs). METHODS: Pulsed wave Doppler of both UAs and the descending aorta was performed at 4-weekly intervals between 14 and 40 weeks of gestation in 209 pregnant women. In datasets with discordant UAs, a linear mixed effects model was used to determine the categorical relationship between the UA pulsatility index (PI) (high, low and average) and the descending aorta PI. RESULTS: Of the 209 cases, 81 had a discordance of greater than 25% in UA PI during one of their visits. There were no differences in birth outcomes between the groups with concordant and discordant UA PIs. In the cases with discordant UA PIs, the descending aorta PI was most strongly associated with both the average UA PI (P = .008), and with the UA with the lower PI (P = .008). CONCLUSIONS: The relationship between blood flow in the descending aorta and UAs is consistent with the law for combining resistances in parallel. Measurements of the descending aorta PI, particularly in a scenario with discordant UAs, may inform the stability of the feto-placental circulation where discordant UA PIs are found.

An MRI approach to assess placental function in healthy humans and sheep.

KEY POINTS: Human placental function is evaluated using non-invasive Doppler ultrasound of umbilical and uterine artery pulsatility indices as measures of resistance in placental vascular beds, while measurement of placental oxygen consumption ( VO2 ) is only possible during Caesarean delivery. This study shows the feasibility of using magnetic resonance imaging (MRI) in utero to measure blood flow and oxygen content in uterine and umbilical vessels to calculate oxygen delivery to and VO2 by the gravid uterus, uteroplacenta and fetus. Normal late gestational human uteroplacental VO2 by MRI was ∼4 ml min-1  kg-1 fetal weight, which was similar to our MRI measurements in sheep and to those previously measured using invasive techniques. Our MRI approach can quantify uteroplacental VO2 , which involves the quantification of maternal- and fetal-placental blood flows, fetal oxygen delivery and VO2 , and the oxygen gradient between uterine- and umbilical-venous blood, providing a comprehensive assessment of placental function with clinical potential. ABSTRACT: It has not been feasible to perform routine clinical measurement of human placental oxygen consumption ( VO2 ) and in vitro studies do not reflect true metabolism in utero. Here we propose an MRI method to non-invasively quantify in utero placental and fetal oxygen delivery ( DO2 ) and VO2 in healthy humans and sheep. Women (n = 20) and Merino sheep (n = 10; 23 sets of measurements) with singleton pregnancies underwent an MRI in late gestation (36 ± 2 weeks and 128 ± 9 days, respectively; mean ± SD). Blood flow (phase-contrast) and oxygen content (T1 and T2 relaxometry) were measured in the major uterine- and umbilical-placental vessels, allowing calculation of uteroplacental and fetal DO2 and VO2 . Maternal DO2 (ml min-1  kg-1 fetus) to the gravid uterus was similar in humans and sheep (human = 54 ± 15, sheep = 53 ± 21, P = 0.854), while fetal DO2 (human = 25 ± 4, sheep = 22 ± 5, P = 0.049) was slightly lower in sheep. Uteroplacental and fetal VO2 (ml min-1  kg-1 fetus; uteroplacental: human = 4.1 ± 1.5, sheep = 3.5 ± 1.9, P = 0.281; fetus: human = 6.8 ± 1.3, sheep = 7.2 ± 1.7, P = 0.426) were similar between species. Late gestational uteroplacental:fetal VO2 ratio did not change with age (human, P = 0.256; sheep, P = 0.121). Human umbilical blood flow (ml min-1  kg-1 fetus) decreased with advancing age (P = 0.008), while fetal VO2 was preserved through an increase in oxygen extraction (P = 0.046). By contrast, sheep fetal VO2 was preserved through stable umbilical flow (ml min-1  kg-1 ; P = 0.443) and oxygen extraction (P = 0.582). MRI derived measurements of uteroplacental and fetal VO2 between humans and sheep were similar and in keeping with prior data obtained using invasive techniques. Taken together, these data confirm the reliability of our approach, which offers a novel clinical 'placental function test'.

Second Trimester Placental Growth Factor Levels and Placental Histopathology in Low-Risk Nulliparous Pregnancies.

OBJECTIVE: Placental growth factor (PlGF) levels are lower at delivery in pregnancies with preeclampsia or fetuses small for gestational age (SGA). These obstetrical complications are typically mediated by placental dysfunction, most commonly related to the specific placental phenotype termed placental maternal vascular malperfusion (MVM). The objective of this study was to determine the relationship between PlGF levels in the second trimester and the development of placental diseases that underlie adverse perinatal outcomes. METHODS: We performed a secondary analysis of the prospective Placental Health Study in unselected healthy nulliparous women (n = 773). Maternal demographic data, Doppler ultrasound measurements, and plasma PlGF levels at 15 to 18 weeks gestation were analyzed for association with pregnancy outcomes and placental pathology following delivery. RESULTS: Low PlGF levels in the second trimester (<10th percentile; <72 pg/mL) was associated with preterm delivery (<37 weeks; 26% vs. 6%, P < 0.001; unadjusted odds ratio (OR) 5.75, 95% CI 3.2-10.5), reduced mean birth weight (2998 vs. 3320 g, P < 0.001), SGA deliveries (25% vs. 11%, P = 0.001; OR 2.6, 95% CI 1.5-4.6), and preeclampsia (7% vs. 2%, P = 0.02; OR 4.3, 95% CI 1.5-12.8) relative to normal PlGF levels (≥10th percentile; ≥72 pg/mL). Low PlGF was associated with lower mean placental weight (447 vs. 471 g, P = 0.01), aberrant cord insertion (25% vs. 12%, P = 0.001) and a pathologic diagnosis of MVM (18% vs. 11%, P = 0.04; OR 1.9, 95% CI 1.01-3.55) but not with other placental pathologies. CONCLUSION: MVM placental pathology and related adverse perinatal outcomes are associated with low PlGF in the early second trimester for healthy nulliparous women.

Stillbirth Following Normal Ultrasound Findings and Maternal Placental Growth Factor Levels.

BACKGROUND: Attempts to reduce the current rate of antepartum stillbirth in the late third trimester have largely focused on the accurate identification of fetal growth restriction. Universal ultrasound significantly increases detection, especially when combined with maternal angiogenic growth factors, but this screening strategy is not well suited to identify umbilical cord pathology. While this poses unique challenges to pregnancy care, the recurrence risk of cord obstruction is low in comparison with many intrinsic placental diseases. CASE: A 30-year-old woman with normal uterine artery Doppler waveforms, fetal growth ultrasounds, and circulating placental growth factor experienced an unexpected third-trimester stillbirth. Placental pathology demonstrated fetal vascular malperfusion and cord hyper-coiling. CONCLUSION: Despite normal placental function, the otherwise healthy fetus is at risk of antepartum stillbirth due to cord-related pathology.

Normal human and sheep fetal vessel oxygen saturations by T2 magnetic resonance imaging.

KEY POINTS: Human fetal Doppler ultrasound and invasive blood gas measurements obtained by cordocentesis or at the time of delivery reveal similarities with sheep (an extensively used model for human fetal cardiovascular physiology). Oxygen saturation (SO2 ) measurements in human fetuses have been limited to the umbilical and scalp vessels, providing little information about normal regional SO2 differences in the fetus. Blood T2 MRI relaxometry presents a non-invasive measure of SO2 in the major fetal vessels. This study presents the first in vivo validation of fetal vessel T2 oximetry against the in vitro T2-SO2 relationship using catheterized sheep fetuses and compares the normal SO2 in the major vessels between the human and sheep fetal circulations. Human fetal vessel SO2 by T2 MRI confirms many similarities with the sheep fetal circulation and is able to demonstrate regional differences in SO2 ; in particular the significantly higher SO2 in the left versus right heart. ABSTRACT: Blood T2 magnetic resonance imaging (MRI) relaxometry non-invasively measures oxygen saturation (SO2 ) in major vessels but has not been validated in fetuses in vivo. We compared the blood T2-SO2 relationship in vitro (tubes) and in vivo (vessels) in sheep, and measured SO2 across the normal human and sheep fetal circulations by T2. Singleton pregnant ewes underwent surgery to implant vascular catheters. In vitro and in vivo sheep blood T2 measurements were related to corresponding SO2 measured using a blood gas analyser, as well as relating T2 and SO2 of human fetal blood in vitro. MRI oximetry was performed in the major vessels of 30 human fetuses at 36 weeks (term, 40 weeks) and 10 fetal sheep (125 days; term, 150 days). The fidelity of in vivo fetal T2 oximetry was confirmed through comparison of in vitro and in vivo sheep blood T2-SO2 relationships (P = 0.1). SO2 was similar between human and sheep fetuses, as was the fetal oxygen extraction fraction (human, 33 ± 11%; sheep, 34 ± 7%; P = 0.798). The presence of streaming in the human fetal circulation was demonstrated by the SO2 gradient between the ascending aorta (68 ± 10%) and the main pulmonary artery (49 ± 9%; P < 0.001). Human and sheep fetal vessel MRI oximetry based on T2 is a validated approach that confirms the presence of streaming of umbilical venous blood towards the heart and brain. Streaming is important in ensuring oxygen delivery to these organs and its disruption may have important implications for organ development, especially in conditions such as congenital heart disease and fetal growth restriction.

Low molecular weight heparin promotes transcription and release of placental growth factor from endothelial cells.

Circulating levels of placental growth factor (PlGF) are significantly reduced in women who develop preeclampsia. Low molecular weight heparin (LMWH) has been shown to acutely elevate circulating PlGF levels in pregnant women at increased risk of preeclampsia. The objective of the current investigation was to determine the mechanisms by which LMWH mediates the extracellular release of PlGF from endothelial cells. Cultured human aortic endothelial cells (HAECs) and human umbilical vein endothelial cells (HUVECs) were exposed to LMWH; PlGF transcription, translation, mobilization, and secretion were then assessed. LMWH significantly increased the release of PlGF from both HAECs and HUVECs. LMWH treatment promoted a significant increase of PlGF-1 mRNA expression in HAECs, accompanied by the intracellular transport and release of PlGF into the conditioned media. LMWH-mediated release of PlGF from HAECs was not directly mediated by extracellular mobilization, synthesis, or stability of PlGF mRNA/protein. LMWH exposure promotes the release of PlGF from endothelial cells through the upregulation of PlGF-1 mRNA expression. Stimulation of circulating PlGF levels by LMWH may be an important mechanism by which LMWH could reduce the risk of preeclampsia or minimize disease severity.NEW & NOTEWORTHY There are few therapeutic options available for the prevention of preeclampsia, a serious hypertensive disorder of pregnancy. Women who subsequently develop preeclampsia exhibit significantly reduced circulating levels of the proangiogenic placental growth factor protein. Low molecular weight heparin (LMWH) has previously been investigated as a preventative therapy against the development of preeclampsia; however, its mechanism of action is not known. The current study determined that LMWH promotes the transcription and release of placental growth factor protein from endothelial cells, providing a mechanistic basis by which LMWH could reduce the risk of preeclampsia or minimize disease severity.