Routine first-trimester pre-eclampsia screening and maternal left ventricular geometry.

OBJECTIVE: Pre-eclampsia (PE) is a pregnancy complication associated with premature cardiovascular disease morbidity and mortality (i.e. before 60 years of age or in the first year postpartum). PE is associated with adverse left ventricular (LV) remodeling in the peri- and postpartum periods, an independent risk factor for cardiovascular disease. This study aimed to compare LV geometry by LV mass (LVM) and LVM index (LVMI) between participants with a high vs low screening risk for preterm PE in the first trimester. METHODS: This was a prospective cohort study of singleton pregnancies between 11 + 0 and 13 + 6 weeks' gestation that underwent screening for preterm PE as part of their routine first-trimester ultrasound assessment at a tertiary center in London, UK, from February 2019 until March 2020. Screening for preterm PE was performed using the Fetal Medicine Foundation algorithm. Participants with a screening risk of ≥ 1 in 50 for preterm PE were classified as high risk and those with a screening risk of ≤ 1 in 500 were classified as low risk. All participants underwent two-dimensional and M-mode transthoracic echocardiography. RESULTS: A total of 128 participants in the first trimester of pregnancy were included in the analysis, with 57 (44.5%) participants screened as low risk and 71 (55.5%) participants as high risk for PE. The risk groups did not vary in maternal age and gestational age at assessment. Maternal body surface area and body mass index were significantly higher in the high-risk group (all P < 0.05). The high-risk participants were significantly more likely to be Afro-Caribbean, nulliparous and have a family history of hypertensive disease in pregnancy as well as other cardiovascular disease (all P < 0.05). In addition, mean arterial blood pressure (P < 0.001), mean heart rate (P < 0.001), median LVM (130.06 (interquartile range, 113.62-150.50) g vs 97.44 (81.68-114.16) g; P < 0.001) and mean LVMI (72.87 ± 12.2 g/m2 vs 57.54 ± 12.72 g/m2 ; P < 0.001) were significantly higher in the high-risk group. Consequently, those in the high-risk group were more likely to have abnormal LV geometry (37.1% vs 7.0%; P < 0.001). CONCLUSIONS: Early echocardiographic assessment in participants at high risk of preterm PE may unmask clinically healthy individuals who are at increased risk for future cardiovascular disease. Adverse cardiac remodeling in the first trimester of pregnancy may be an indicator of decreased cardiovascular reserve and subsequent dysfunctional cardiovascular adaptation in pregnancy. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Maternal ethnicity and socioeconomic deprivation: influence on adverse pregnancy outcomes.

OBJECTIVE: To evaluate the relative importance of ethnicity and socioeconomic deprivation in determining the likelihood and prevalence of placentally derived composite of adverse pregnancy outcomes (CAPO) and composite of severe adverse pregnancy outcomes (CAPO-S). METHODS: This was a single-center retrospective cohort study of data obtained in a tertiary maternity unit. Data regarding ethnicity and socioeconomic deprivation (as measured with indices of multiple deprivation) were collected for 13 165 singleton pregnancies screened routinely in the first trimester for pre-eclampsia using the Fetal Medicine Foundation combined risk-assessment algorithm. CAPO was defined as the presence of one or more interrelated outcomes associated with placental dysfunction, namely, hypertensive disorders of pregnancy, preterm birth, birth weight ≤ 10th centile and stillbirth. CAPO-S was defined as the presence of one or more of the following: hypertensive disorders of pregnancy at < 37 + 0 weeks, preterm birth at < 34 + 0 weeks, birth weight ≤ 5th centile and stillbirth at < 37 + 0 weeks. RESULTS: The prevalence of CAPO was 16.3% in white women, 29.3% in black women and 29.3% in South Asian women. However, half (51.7%) of all CAPO cases occurred in white women. There was a strong interaction between ethnicity and socioeconomic deprivation, with a correlation coefficient of -0.223. Both ethnicity and socioeconomic deprivation influenced the prevalence of CAPO and CAPO-S, with the contribution of ethnicity being the strongest. CONCLUSIONS: Black and Asian ethnicity, as well as socioeconomic deprivation, influence the prevalence of placenta-mediated adverse pregnancy outcomes. Despite this, most adverse pregnancy outcomes occur in white women, who represent the majority of the population and are also affected by socioeconomic deprivation. For these reasons, inclusion of socioeconomic deprivation should be considered in early pregnancy risk assessment for placenta-mediated CAPO. © 2024 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Origen étnico materno y privación socioeconómica: influencia en los resultados adversos del embarazo OBJETIVO: Evaluar la importancia relativa de la etnia y la privación socioeconómica en la determinación de la probabilidad y la prevalencia de los resultados adversos compuestos del embarazo relacionados con la placenta (CAPO, por sus siglas en inglés) y los resultados adversos compuestos graves del embarazo (CAPO­S). MÉTODOS: Se trata de un estudio de cohortes retrospectivo unicéntrico de datos obtenidos en una unidad de maternidad terciaria. Se recopilaron datos relativos al origen étnico y la privación socioeconómica (mediante índices de privación múltiple) de 13 165 embarazos únicos sometidos a cribado rutinario en el primer trimestre para detectar la preeclampsia mediante el algoritmo combinado de evaluación de riesgos de la Fetal Medicine Foundation. Los CAPO se definieron como la presencia de uno o más resultados interrelacionados asociados con una disfunción placentaria, como trastornos hipertensivos del embarazo, parto prematuro, peso al nacer ≤10° percentil y éxitus fetal. Los CAPO­S se definieron como la presencia de uno o más de los siguientes: trastornos hipertensivos del embarazo <37+0 semanas, parto prematuro a <37+0 semanas, peso al nacer ≤5° percentil y éxitus fetal a <37+0 semanas. RESULTADOS: La prevalencia de los CAPO fue del 16,3% en las mujeres blancas, del 29,3% en las negras y del 29,3% en las sudasiáticas. Sin embargo, la mitad (51,7%) de todos los casos de CAPO se produjeron en mujeres blancas. Hubo una fuerte interacción entre etnia y privación socioeconómica, con un coeficiente de correlación de −0,223. Tanto la etnia como la privación socioeconómica influyeron en la prevalencia de los CAPO y CAPO­S, siendo la contribución de la etnia la más fuerte. CONCLUSIONES: Las etnias negra y asiática, así como la privación socioeconómica, influyen en la prevalencia de resultados adversos del embarazo relacionados con la placenta. A pesar de ello, la mayoría de los resultados adversos del embarazo se producen en mujeres blancas, que representan la mayoría de la población y también se ven afectadas por la privación socioeconómica. Por estas razones, debe considerarse la inclusión de la privación socioeconómica en la evaluación temprana del riesgo de CAPO relacionados con la placenta durante el embarazo.

Advances in pathogenesis of preeclampsia.

PURPOSE: Preeclampsia is a major cause of health problems for both pregnant women and unborn babies worldwide. However, the underlying causes of preeclampsia are not fully understood, leading to limited effective treatments. The goal of this study is to enhance our knowledge of its causes, devise prevention strategies, and develop treatments. METHODS: We performed a systematic literature search. Six models regarding the pathogenesis of preeclampsia are discussed in this review. RESULTS: This review focuses on the latest advancements in understanding preeclampsia's origins. Preeclampsia is a complex condition caused by various factors, processes, and pathways. Reduced blood flow and oxygen to the uterus and placenta, heightened inflammatory reactions, immune imbalances, altered genetic changes, imbalanced blood vessel growth factors, and disrupted gut bacteria may contribute to its development. CONCLUSION: Preeclampsia is thought to result from the interplay of these factors.

Connecting G protein-coupled estrogen receptor biomolecular mechanisms with the pathophysiology of preeclampsia: a review.

BACKGROUND: Throughout the course of pregnancy, small maternal spiral arteries that are in contact with fetal tissue undergo structural remodeling, lose smooth muscle cells, and become less responsive to vasoconstrictors. Additionally, placental extravillous trophoblasts invade the maternal decidua to establish an interaction between the fetal placental villi with the maternal blood supply. When successful, this process enables the transport of oxygen, nutrients, and signaling molecules but an insufficiency leads to placental ischemia. In response, the placenta releases vasoactive factors that enter the maternal circulation and promote maternal cardiorenal dysfunction, a hallmark of preeclampsia (PE), the leading cause of maternal and fetal death. An underexplored mechanism in the development of PE is the impact of membrane-initiated estrogen signaling via the G protein-coupled estrogen receptor (GPER). Recent evidence indicates that GPER activation is associated with normal trophoblast invasion, placental angiogenesis/hypoxia, and regulation of uteroplacental vasodilation, and these mechanisms could explain part of the estrogen-induced control of uterine remodeling and placental development in pregnancy. CONCLUSION: Although the relevance of GPER in PE remains speculative, this review provides a summary of our current understanding on how GPER stimulation regulates some of the features of normal pregnancy and a potential link between its signaling network and uteroplacental dysfunction in PE. Synthesis of this information will facilitate the development of innovative treatment options.

Maternal body mass index, birthweight, and placental glucose metabolism: evidence for a role of placental hexokinase.

BACKGROUND: The principal fetal energy source is glucose provided by the placental transfer of maternal glucose. However, the placenta's glucose consumption exhibits considerable variation. Hexokinase is the first and one of the rate-limiting enzymes of glycolysis that phosphorylates glucose to glucose-6-phosphate. The role of placental hexokinase activity in human placental glucose metabolism is unknown. OBJECTIVE: This study aimed to test the hypothesis that placental hexokinase activity is related to maternal body mass index, placental glucose uptake and consumption, and birthweight. STUDY DESIGN: Overall, 67 healthy pregnant participants at term were included in this study at Oslo University Hospital, Oslo, Norway. Placental hexokinase activity was measured by using a colorimetric assay. The mass of glucose taken up by the uteroplacental unit and the fetus was obtained by measuring arteriovenous glucose differences combined with Doppler assessment of uterine and umbilical blood flow. Blood samples were obtained from the maternal radial artery, uterine vein, and umbilical artery and vein. The uteroplacental glucose consumption constituted the difference between uteroplacental and fetal glucose uptakes. The Spearman rank correlation was performed for statistical analyses to study the correlation of placental hexokinase activity (milliunit per milligram of protein) with prepregnancy body mass index, maternal glucose and insulin, birthweight, uteroplacental glucose uptake and consumption, and fetal glucose uptake (micromole per minute). Partial rank correlation analysis was performed when controlling for hours of fasting or placental weight. RESULTS: Hexokinase activity was detectable in all placental tissue samples. The mean activity was 19.6 (standard deviation, 4.64) mU/mg protein. Placental hexokinase activity correlated positively with prepregnancy body mass index (Spearman rho=0.33; P=.006). On controlling for hours of fasting, hexokinase activity showed positive correlations with both maternal glucose (r=0.30; P=.01) and insulin (r=0.28; P=.02). Hexokinase activity was positively correlated with uteroplacental glucose uptake (Spearman rho=0.31; P=.01) and consumption (Spearman rho=0.28; P=.02). Hexokinase activity did not correlate with fetal glucose uptake. On controlling for placental weight, hexokinase activity showed a positive correlation with birthweight (r=0.31; P=.01). CONCLUSION: Our findings suggest that placental hexokinase, being crucial for uteroplacental retention of glucose for disposition, is related to both maternal body mass index and birthweight independent of placental weight. Placental hexokinase may play a central role in the relationship between maternal glucose dysregulation and fetal growth. Thus, the current study supports the need to develop clinically useful tools to assess the metabolic properties of the placenta.

Ultrasound evaluation of normal rhesus macaque fetal biometry and uteroplacental hemodynamics.

Nonhuman primates are important preclinical models for translational, reproductive, and developmental science. Clinical evaluation of human fetal development is performed using standard sonographic-derived fetal biometry, assessments of amniotic fluid, and uteroplacental hemodynamics. These noninvasive in utero measurements provide important information regarding fetal growth and pregnancy well-being. Abnormalities in fetal growth, amniotic fluid volume, or placental vascular function are associated with placental insufficiency and adverse perinatal outcomes including stillbirth. The fetal biometric parameters most commonly assessed are biparietal diameter, head circumference, abdominal circumference, and femur diaphysis length. Evaluation of amniotic fluid volume includes measuring the fluid in four quadrants of the uterus to generate an Amniotic Fluid Index. Measures of uteroplacental hemodynamics typically include doppler assessment of the umbilical artery and ductus venosus, but can also include interrogation of the uterine artery and umbilical vein. In this study, we compile prenatal ultrasound data of fetal biometry, amniotic fluid measurements, and uteroplacental hemodynamics obtained from pregnancy studies conducted at the Oregon National Primate Research Center. The data included are from control unperturbed pregnant animals who have not undergone in utero experimental manipulations. This is the first report of comprehensive sonographic measurements following standardized clinical obstetric protocols utilized in rhesus macaques. The outcome is a large, prenatal ultrasound resource to be used by laboratory animal researchers in future nonhuman primate pregnancy studies for antenatal assessment.

Establishment of a new equation to estimate gestational age in female dogs.

The objectives of this study were to propose a statistical model to predict the behaviour of the thickness of the uteroplacental junction as a function of the gestation period in female dogs and to determine the relationship between the thickness of the placenta and gestational age in healthy female dogs whose pregnancies had elapsed without maternal-fetal alterations. Eight Border Collie female dogs were selected, aged 3-6 (4.48 ± 0.89) and weighing 16-22 kg (19.06 ± 1.9 kg). Female dogs with gestational ages from 20 to 62 days were examined weekly using B-mode ultrasonography. Ultrasound measurements of the uteroplacental junction were organized into four distinct groups: GT1 (27-36 days of gestation), GT2 (37-46 days of gestation), GT3 (47-56 days of gestation) and GT4 (57-62 days of gestation). Based on multiple linear regression, a statistical model was proposed to predict the behaviour of the thickness of the uteroplacental junction (y) as a function of the length of gestation (x) in female dogs, where b0 is the intercept (linear coefficient) and bp is the slope of the predictors. The analysis relating GT, age and weight could predict placental thickness and resulted in a statistically significant model [F(1,28) = 153,736; p < .001; R2 = .846], but only that relating the length of pregnancy (ß = .92; t = 12.399; p < .001) predicted the thickness of the placenta according to the equation y = b0 + bp.x1 [(thickness in cm) = ß -0.3 + 0.019 × (gestation time in days)]. Only in GT4 was there no correlation between placentas within the same pregnancy (p > .05). Based on the close relationship between the development of the uteroplacental junction thickness during pregnancy and gestational age, it is possible to develop a new tool to complement gestational ultrasound evaluation in female dogs. This is important because it allows better placental evaluation in the search for significant alterations that could compromise maternal-fetal health.

Ca2+-Activated K+ Channels and the Regulation of the Uteroplacental Circulation.

Adequate uteroplacental blood supply is essential for the development and growth of the placenta and fetus during pregnancy. Aberrant uteroplacental perfusion is associated with pregnancy complications such as preeclampsia, fetal growth restriction (FGR), and gestational diabetes. The regulation of uteroplacental blood flow is thus vital to the well-being of the mother and fetus. Ca2+-activated K+ (KCa) channels of small, intermediate, and large conductance participate in setting and regulating the resting membrane potential of vascular smooth muscle cells (VSMCs) and endothelial cells (ECs) and play a critical role in controlling vascular tone and blood pressure. KCa channels are important mediators of estrogen/pregnancy-induced adaptive changes in the uteroplacental circulation. Activation of the channels hyperpolarizes uteroplacental VSMCs/ECs, leading to attenuated vascular tone, blunted vasopressor responses, and increased uteroplacental blood flow. However, the regulation of uteroplacental vascular function by KCa channels is compromised in pregnancy complications. This review intends to provide a comprehensive overview of roles of KCa channels in the regulation of the uteroplacental circulation under physiological and pathophysiological conditions.

Preeclampsia and diabetes mellitus.

OBJECTIVE: The purpose of this paper is to provide a review of recent research on the relationship between preeclampsia and diabetes mellitus in pregnancy. METHODOLOGY: A structured search for literary sources in PubMed and ScienceDirect databases using keywords, followed by a selection of papers based on solid methodology. RESULTS: Preeclampsia is a serious condition, which complicates 2-7% of pregnancies. It causes maternal complications (organ dysfunction) and fetal complications (pathological haemodynamic parameters of the uteroplacental unit and fetal growth restriction). Pregnant women with pregestational diabetes have a 2- and 4-times higher risk of developing preeclampsia and the ones with gestational diabetes have 1.3-times higher risk. The main identified risk factors are inadequate compensation of diabetes, diabetic nephropathy, retinopathy and the duration of diabetes. To minimalize the risk of developing preeclampsia, a composite screening has been implemented. With a positive result a preventive use of acetylsalicylic acid from at the latest 16 and up until the 36th week is advised. Preeclampsia is also a risk factor for developing diabetes mellitus and other cardiovascular diseases later in life. For that reason, a long-term dispensary of women who had preeclampsia in pregnancy is recommended.

Chronic hypertension and superimposed preeclampsia: screening and diagnosis.

Superimposed preeclampsia complicates about 20% of pregnancies in women with chronic hypertension and is associated with increased maternal and perinatal morbidity compared with preeclampsia alone. Distinguishing superimposed preeclampsia from chronic hypertension can be challenging because, in chronic hypertension, the traditional criteria for the diagnosis of preeclampsia, hypertension, and significant proteinuria can often predate the pregnancy. Furthermore, the prevalence of superimposed preeclampsia is unlikely to be uniformly distributed across this high-risk group but is related to the severity of preexisting endothelial dysfunction. This has led to interest in identifying biomarkers that could help in screening and diagnosis of superimposed preeclampsia and in the stratification of risk in women with chronic hypertension. Elevated levels of uric acid and suppression of other renal biomarkers, such as the renin-angiotensin aldosterone system, have been demonstrated in women with superimposed preeclampsia but perform only modestly in its prediction. In addition, central to the pathogenesis of preeclampsia is a tendency toward an antiangiogenic state thought to be triggered by an impaired placenta and, ultimately, contributing to the endothelial dysfunction pathognomonic of the disease. In the general obstetrical population, angiogenic factors, such as soluble fms-like tyrosine kinase-1 and placental growth factor, have shown promise in the prediction of preeclampsia. However, soluble fms-like tyrosine kinase-1 and placental growth factor are impaired in women with chronic hypertension irrespective of whether they develop superimposed preeclampsia. Therefore, the differences in levels are less discriminatory in the prediction of superimposed preeclampsia compared with the general obstetrical population. Alternative biomarkers to the angiogenic and renal factors include those of endothelial dysfunction. A characteristic of both preeclampsia and chronic hypertension is an exaggerated systemic inflammatory response causing or augmenting endothelial dysfunction. Thus, proinflammatory mediators, such as tumor necrosis factor-α, interleukin-6, cell adhesion molecules, and endothelin, have been investigated for their role in the screening and diagnosis of superimposed preeclampsia in women with chronic hypertension. To date, the existing limited evidence suggests that the differences between those who develop superimposed preeclampsia and those who do not are, as with angiogenic factors, also modest and not clinically useful for the stratification of women with chronic hypertension. Finally, pro-B-type natriuretic peptide is regarded as a sensitive marker of early cardiac dysfunction that, in women with chronic hypertension, may predate the pregnancy. Thus, it has been proposed that pro-B-type natriuretic peptide could give insight as to the ability of women with chronic hypertension to adapt to the hemodynamic requirements of pregnancy and, subsequently, their risk of developing superimposed preeclampsia. Although higher levels of pro-B-type natriuretic peptide have been demonstrated in women with superimposed preeclampsia compared with those without, current evidence suggests that pro-B-type natriuretic peptide is not a predictor for the disease. The objectives of this review are to, first, discuss the current criteria for the diagnosis of superimposed preeclampsia and, second, to summarize the evidence for these potential biomarkers that may assist in the diagnosis of superimposed preeclampsia.

Preeclampsia and eclampsia: the conceptual evolution of a syndrome.

Preeclampsia, one of the most enigmatic complications of pregnancy, is considered a pregnancy-specific disorder caused by the placenta and cured only by delivery. This article traces the condition from its origins-once thought to be a disease of the central nervous system, recognized by the occurrence of seizures (ie, eclampsia)-to the present time when preeclampsia is conceptualized primarily as a vascular disorder. We review the epidemiologic data that led to the recommendation to use diastolic hypertension and proteinuria as diagnostic criteria, as their combined presence was associated with an increased risk of fetal death and the birth of small-for-gestational-age neonates. However, preeclampsia is a multisystemic disorder with protean manifestations, and the condition can be present even in the absence of hypertension and proteinuria. Toxins gaining access to the maternal circulation have been proposed to mediate the clinical manifestations-hence, the term "toxemia of pregnancy," which was used for several decades. The search for putative toxins has challenged investigators for more than a century, and a growing body of evidence suggests that products of an ischemic or a stressed placenta are responsible for the vascular changes that characterize this syndrome. The discovery that the placenta can produce antiangiogenic factors, which regulate endothelial cell function and induce intravascular inflammation, has been a major step forward in the understanding of preeclampsia. We view the release of antiangiogenic factors by the placenta as an adaptive response to improve uterine perfusion by modulating endothelial function and maternal cardiovascular performance. However, this homeostatic response can become maladaptive and lead to damage of target organs during pregnancy or the postpartum period. Early-onset preeclampsia has many features in common with atherosclerosis, whereas late-onset preeclampsia seems to result from a mismatch of fetal demands and maternal supply, that is, a metabolic crisis. Preeclampsia, as it is understood today, is essentially vascular dysfunction unmasked or caused by pregnancy. A subset of patients diagnosed with preeclampsia are at greater risk of the subsequent development of hypertension, ischemic heart disease, heart failure, vascular dementia, and end-stage renal disease. However, these adverse events may be the result of a preexisting vascular pathologic process; it is not known if the occurrence of preeclampsia increases the baseline risk. Therefore, the understanding, prediction, prevention, and treatment of preeclampsia are healthcare priorities.

Routine first-trimester pre-eclampsia screening and risk of preterm birth.

OBJECTIVES: Preterm birth (PTB) is a major public health problem worldwide. It can occur spontaneously or be medically indicated for obstetric complications, such as pre-eclampsia (PE) or fetal growth restriction. The main objective of this study was to investigate whether there is a shared uteroplacental etiology in the first trimester of pregnancy across PTB subtypes. METHODS: This was a retrospective cohort study of singleton pregnancies that underwent screening for preterm PE as part of their routine first-trimester ultrasound assessment at a tertiary center in London, UK, between March 2018 and December 2020. Screening for preterm PE was performed using the Fetal Medicine Foundation algorithm, which includes maternal factors, mean arterial pressure (MAP), uterine artery pulsatility index (UtA-PI) and pregnancy-associated plasma protein-A (PAPP-A). Women with a risk of ≥ 1 in 50 for preterm PE were classified as high risk and offered prophylactic aspirin (150 mg once a day) and serial ultrasound assessments. The following delivery outcomes were evaluated: PTB < 37 weeks, iatrogenic PTB (iPTB) and spontaneous PTB (sPTB). Logistic regression analyses were performed to assess the association of PTB, iPTB and sPTB with an increased risk of preterm PE. A model for prediction of PTB < 37 weeks and < 33 weeks was developed and its performance was compared with that of an existing model in the literature. RESULTS: A total of 11 437 women were included in the study, of whom 475 (4.2%) had PTB. Of these, 308 (64.8%) were sPTB and 167 (35.2%) were iPTB. Patients with PTB had a higher body mass index, were more likely to be of black or Asian ethnicity, be smokers, have pregestational hypertension or diabetes, or have a history of previous PTB. They also had higher MAP (87.7 vs 86.0 mmHg, P < 0.0001), higher UtA-PI multiples of the median (MoM) (0.99 vs 0.92, P < 0.0001) and lower PAPP-A MoM (0.89 vs 1.08, P < 0.0001) compared to women with a term birth. In women at high risk of PE, the odds ratio for iPTB was 6.0 (95% CI, 4.29-8.43; P < 0.0001) and that for sPTB was 2.0 (95% CI, 1.46-2.86; P < 0.0001). A prediction model for PTB < 37 weeks and < 33 weeks, developed based on this cohort, included previous PTB, black ethnicity, chronic hypertension, diabetes mellitus, PAPP-A MoM and UtA-PI MoM. The performance of the model was similar to that of an existing first-trimester prediction model for PTB < 33 weeks (area under the curve, 0.704 (95% CI, 0.653-0.754) vs 0.694 (95% CI, 0.643-0.746)). CONCLUSIONS: Increased first-trimester risk for uteroplacental dysfunction was associated with both iPTB and sPTB, implying a shared etiological pathway. The same factors used to predict PE risk show acceptable discrimination to predict PTB at < 33 weeks. Women at high risk of uteroplacental dysfunction may warrant additional monitoring and management for an increased risk of sPTB. © 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

First-trimester ultrasound diagnostic features of placenta accreta spectrum in low-implantation pregnancy.

OBJECTIVE: Low-implantation pregnancy (LIP) is an important marker for the diagnosis of placenta accreta spectrum (PAS) in the first trimester. Many grayscale and color Doppler ultrasound markers of PAS have been defined in the second and third trimesters of pregnancy, but have not been studied in the first trimester. The aim of this study was to determine whether PAS sonographic markers could be used in the first trimester to differentiate patients with LIP who develop PAS from those who do not. METHODS: This was a retrospective case-control study of women who delivered at our institution between 2009 and 2019. Cases were women with PAS who delivered by Cesarean hysterectomy and who had undergone first-trimester ultrasound demonstrating LIP. Controls were women with persistent placenta previa without PAS who delivered by Cesarean section without postpartum hemorrhage and who had undergone first-trimester ultrasound demonstrating LIP. Sonographic images were reviewed by an investigator blinded to pregnancy outcome and ultrasound reports. Images were reviewed for presence of abnormal uteroplacental interface, increased lower uterine segment hypervascularity and placental lacunae, with or without swirling on grayscale or color Doppler ultrasound. RESULTS: Following review of the electronic health records, 21 cases and 46 controls met the inclusion criteria. Placental lacunae were present in 18/21 (85.7%) cases and 7/46 (15.2%) controls (odds ratio (OR), 33.4; 95% CI, 7.7-144.4; P < 0.001). The number of lacunae was significantly higher in cases compared with controls, with a median of five lacunae present in cases compared with a median of one lacuna in controls (P < 0.001). The median size of the lacunae was also significantly larger in cases compared with controls, measuring 10.03 (interquartile range (IQR), 7.3-12.05) mm and 4.15 (IQR, 4.05-5.05) mm, respectively (P = 0.001). Lacunae swirling on grayscale or color Doppler ultrasound was noted only in PAS cases, with 10/12 (83.3%) having swirling on grayscale ultrasound and 12/12 (100%) having swirling on color Doppler (P < 0.001). Presence of an abnormal uteroplacental interface was also observed only in PAS cases, at a rate of 17/20 (85.0%) (P < 0.001). Lower uterine segment (uterovesical, subplacental and/or intraplacental) hypervascularity was present in 14/14 (100%) cases and only 1/12 (8.3%) controls (P < 0.001). CONCLUSION: In women at risk of PAS, ultrasound markers of PAS can and should be assessed as early as in the first trimester. The use of a first-trimester prenatal ultrasound screening protocol and standardized approach to ultrasound examination in at-risk mothers may help increase detection of PAS and enable planning for optimal management of affected pregnancies. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Potassium Channels in the Uterine Vasculature: Role in Healthy and Complicated Pregnancies.

A progressive increase in maternal uterine and placental blood flow must occur during pregnancy to sustain the development of the fetus. Changes in maternal vasculature enable an increased uterine blood flow, placental nutrient and oxygen exchange, and subsequent fetal development. K+ channels are important modulators of vascular function, promoting vasodilation, inducing cell proliferation, and regulating cell signaling. Different types of K+ channels, such as Ca2+-activated, ATP-sensitive, and voltage-gated, have been implicated in the adaptation of maternal vasculature during pregnancy. Conversely, K+ channel dysfunction has been associated with vascular-related complications of pregnancy, including intrauterine growth restriction and pre-eclampsia. In this article, we provide an updated and comprehensive literature review that highlights the relevance of K+ channels as regulators of uterine vascular reactivity and their potential as therapeutic targets.

Something old, something new: digital quantification of uterine vascular remodelling and trophoblast plugging in historical collections provides new insight into adaptation of the utero-placental circulation.

STUDY QUESTION: What is the physiological extent of vascular remodelling in and trophoblast plugging of the uterine circulation across the first half of pregnancy? SUMMARY ANSWER: All levels of the uterine vascular tree (arcuate, radial and spiral arteries (SAs)) dilate ∼2.6- to 4.3-fold between 6 and 20 weeks of gestation, with significant aggregates of trophoblasts persisting in the decidual and myometrial parts of SAs beyond the first trimester. WHAT IS KNOWN ALREADY: In early pregnancy, endovascular trophoblasts form 'plugs' in the SAs, transiently inhibiting blood flow to the placenta, whilst concurrently the uterine vasculature undergoes significant adaption to facilitate increased blood delivery to the placenta later in gestation. These processes are impaired in pregnancy disorders, but quantitative understanding of the anatomical changes even in normal pregnancy is poor. STUDY DESIGN, SIZE, DURATION: Serial sections of normal placentae in situ (n = 22) of 6.1-20.5 weeks of gestation from the Boyd collection and Dixon collection (University of Cambridge, UK) were digitalized using a slide scanner or Axio Imager.A1 microscope. PARTICIPANTS/MATERIALS, SETTING, METHODS: Spiral (n = 45), radial (n = 40) and arcuate (n = 39) arteries were manually segmented. Using custom-written scripts for Matlab® software, artery dimensions (Feret diameters; major axes; luminal/wall area) and endovascular trophoblast plug/aggregate (n = 24) porosities were calculated. Diameters of junctional zone SAs within the myometrium (n = 35) were acquired separately using a micrometre and light microscope. Decidual thickness and trophoblast plug depth was measured using ImageJ. MAIN RESULTS AND THE ROLE OF CHANCE: By all measures, radial and arcuate artery dimensions progressively increased from 6.1 to 20.5 weeks (P < 0.01). The greatest increase in SA calibre occurred after 12 weeks of gestation. Trophoblast aggregates were found to persist within decidual and myometrial parts of SA lumens beyond the first trimester, and up to 18.5 weeks of gestation, although those present in the second trimester did not appear to prevent the passage of red blood cells to the intervillous space. Trophoblasts forming these aggregates became more compact (decreased in porosity) over gestation, whilst channel size between cells increased (P = 0.01). Decidual thickness decreased linearly over gestation (P = 0.0003), meaning plugs occupied an increasing proportion of the decidua (P = 0.02). LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: Although serial sections were assessed, two-dimensional images cannot completely reflect the three-dimensional properties and connectivity of vessels and plugs/aggregates. Immersion-fixation of the specimens means that vessel size may be under-estimated. WIDER IMPLICATIONS OF THE FINDINGS: Uterine vascular remodelling and trophoblast plug dispersion is a progressive phenomenon that is not completed by the end of the first trimester. Our quantitative findings support the concept that radial arteries present a major site of resistance until mid-gestation. Their dimensional increase at 10-12 weeks of gestation may explain the rapid increase in blood flow to the placenta observed by others at ∼13 weeks. Measured properties of trophoblast plugs suggest that they will impact on the resistance, shear stress and nature of blood flow within the utero-placental vasculature until mid-gestation. The presence of channels within plugs will likely lead to high velocity flow streams and thus increase shear stress experienced by the trophoblasts forming the aggregates. Quantitative understanding of utero-placental vascular adaptation gained here will improve in silico modelling of utero-placental haemodynamics and provide new insights into pregnancy disorders, such as fetal growth restriction. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by a Royal Society Te Aparangi Marsden Grant [18-UOA-135]. A.R.C. is supported by a Rutherford Discovery Fellowship [14-UOA-019]. The authors have no conflict of interest to declare.

Error traps in anesthesia for fetal interventions.

A wide range of fetal interventions are being performed worldwide to save the fetus's life, prevent permanent fetal organ damage, and allow a successful transition to extrauterine life. However, these are invasive procedures and can be associated with serious complications. This article focuses on promoting a culture of safety by highlighting five common error traps while anesthetizing patients for fetal interventions. They include failure to preserve uteroplacental perfusion and gas exchange, failure to achieve adequate uterine relaxation prior to hysterotomy, failure to monitor the fetus and prepare for fetal/neonatal resuscitation, failure to prepare for maternal hemorrhage, and failure to promptly treat uterine atony. Practical tips for avoiding these serious complications will also be discussed.

Uteroplacental Circulation in Normal Pregnancy and Preeclampsia: Functional Adaptation and Maladaptation.

Uteroplacental blood flow increases as pregnancy advances. Adequate supply of nutrients and oxygen carried by uteroplacental blood flow is essential for the well-being of the mother and growth/development of the fetus. The uteroplacental hemodynamic change is accomplished primarily through uterine vascular adaptation, involving hormonal regulation of myogenic tone, vasoreactivity, release of vasoactive factors and others, in addition to the remodeling of spiral arteries. In preeclampsia, hormonal and angiogenic imbalance, proinflammatory cytokines and autoantibodies cause dysfunction of both endothelium and vascular smooth muscle cells of the uteroplacental vasculature. Consequently, the vascular dysfunction leads to increased vascular resistance and reduced blood flow in the uteroplacental circulation. In this article, the (mal)adaptation of uteroplacental vascular function in normal pregnancy and preeclampsia and underlying mechanisms are reviewed.

[Uteroplacental blood flow in maternal diabetes mellitus]. / Matochno-platsentarnyi krovotok pri sakharnom diabete u materi.

Various uteroplacental blood flow disorders, their diagnosis, and correction, especially if the maternal obstetric history is burdened by endocrinopathy, still remain an urgent obstetric problem. OBJECTIVE: To study blood flow in the vessel-red blood cell segment and to search for changes in both the vessels of the villous tree of the placenta and uterus and the properties of blood corpuscles, by using modern microscopy methods (scanning probe microscopy, atomic force microscopy). MATERIAL AND METHODS: For macroscopic and microscopic examinations, fragments of the placenta, umbilical cord, and uterus were taken; venous blood samples were collected from patients without endocrinopathy, with gestational diabetes mellitus (GDM) or type 1 and type 2 diabetes mellitus (DM) prior to delivery. The data were statistically processed using both parametric (Student's t-test) and nonparametric (Fisher's exact test) methods. RESULTS: The authors found that microangiopathy and other metabolic changes in diabetes mellitus could lead to villous stromal sclerosis, the appearance of intermediate villi, changes in blood vessel shape, relief tortuosity, depth, and area, endothelial cell destruction, stasis, and thrombosis. In these endocrinopathies, there were also changes in maternal red blood cells: their polymorphism was observed and geometric parameters and deformability were impaired. In this case, cell shape impairment correlated with the severity of the above described vascular complications. CONCLUSION: The use of modern microscopy methods makes it possible to diagnose uteroplacental blood flow changes even in early pregnancy and to prevent the progression of uteroplacental blood flow disorders and placental insufficiency.

Safety and efficacy of sildenafil citrate to reduce operative birth for intrapartum fetal compromise at term: a phase 2 randomized controlled trial.

BACKGROUND AND OBJECTIVE: Sildenafil citrate is a vasodilator used in erectile dysfunction and pulmonary hypertension. We tested whether it reduces emergency operative births for fetal compromise and improves fetal or uteroplacental perfusion in labor in a phase 2 double-blind randomized controlled trial. STUDY DESIGN: Women at term in early labor or undergoing scheduled induction of labor at Mater Mother's Hospital, Brisbane, Australia, were randomly allocated 50 mg of sildenafil citrate orally 8 hourly up to 150 mg or placebo. Intrapartum fetal monitoring followed Royal Australian and New Zealand College of Obstetricians and Gynaecologists guidelines. Primary outcomes were (1) emergency operative birth (by cesarean delivery or instrumental vaginal birth) for intrapartum fetal compromise and (2) mean indices of fetal and uteroplacental perfusion using Doppler ultrasound. Analysis was by intention-to-treat. TRIAL REGISTRATION NUMBER: ANZCTRN12615000319572 RESULTS: Between September 2015 and January 2019, 300 women were randomized equally to sildenafil citrate or placebo. Sildenafil citrate reduced the risk of emergency operative birth by 51% (18% vs 36.7%; relative risk, 0.49, 95% confidence interval, 0.33-0.73, P=.0004, number needed to treat = 5 [3-11]). There was no difference in indices of fetal and uteroplacental perfusion, but these were ascertained in only 71 women. Sildenafil citrate reduced the risk of meconium-stained liquor or pathologic fetal heart rate patterns by 43% (25.3% vs 44.7%; relative risk, 0.57, 95% confidence interval, 0.41-0.79, P=.0005), but its effects on fetal scalp sampling rates (2.0% vs 6.7%; relative risk, 0.30, 95% confidence interval, 0.08-1.07, P=.06) and adverse neonatal outcome (20.7% vs 21.3%; relative risk, 0.97, 95% confidence interval, 0.62-1.50, P=.89) were inconclusive. Only 3.6% of maternal levels of sildenafil citrate or its metabolite were detected in cord blood. No differences in maternal adverse events were seen. CONCLUSION: Sildenafil citrate reduced operative birth for intrapartum fetal compromise, but much larger phase 3 trials of its effects on mother and child are needed before it can be routinely recommended.

Reduced right ventricular function on cardiovascular magnetic resonance imaging is associated with uteroplacental impairment in tetralogy of Fallot.

BACKGROUND: Maternal right ventricular (RV) dysfunction (measured by echocardiography) is associated with impaired uteroplacental circulation, however echocardiography has important limitations in the assessment of RV function. We therefore aimed to investigate the association of pre-pregnancy RV and left ventricular (LV) function measured by cardiovascular magnetic resonance with uteroplacental Doppler flow parameters in pregnant women with repaired Tetralogy of Fallot (ToF). METHODS: Women with repaired ToF were examined, who had been enrolled in a prospective multicenter study of pregnant women with congenital heart disease. Clinical data and CMR evaluation before pregnancy were compared with uteroplacental Doppler parameters at 20 and 32 weeks gestation. In particular, pulsatility index (PI) of uterine and umbilical artery were studied. RESULTS: We studied 31 women; mean age 30 years, operated at early age. Univariable analyses showed that reduced RV ejection fraction (RVEF; P = 0.037 and P = 0.001), higher RV end-systolic volume (P = 0.004) and higher LV end-diastolic and end-systolic volume (P = 0.001 and P = 0.003, respectively) were associated with higher uterine or umbilical artery PI. With multivariable analyses (corrected for maternal age and body mass index), reduced RVEF before pregnancy remained associated with higher umbilical artery PI at 32 weeks (P = 0.002). RVEF was lower in women with high PI compared to women with normal PI during pregnancy (44% vs. 53%, p = 0.022). LV ejection fraction was not associated with uterine or umbilical artery PI. CONCLUSIONS: Reduced RV function before pregnancy is associated with abnormal uteroplacental Doppler flow parameters. It could be postulated that reduced RV function on pre-pregnancy CMR (≤2 years) is a predisposing factor for impaired placental function in women with repaired ToF.