Lower uterine segment scar assessment at 11-14 weeks' gestation to screen for placenta accreta spectrum in women with prior Cesarean delivery.

OBJECTIVES: To validate prospectively transvaginal ultrasound assessment of the lower uterine segment (LUS) scar at the time of first-trimester screening in women with previous Cesarean section (CS) and to determine its feasibility and accuracy in stratifying women according to the risk for placenta accreta spectrum (PAS) disorder. METHODS: Women with a history of CS were recruited between 11 + 0 and 13 + 6 weeks' gestation and underwent LUS scar assessment using transvaginal ultrasound. A standardized midsagittal plane, which included the cervicoisthmic canal (CIC), the uterine scar and the placental site, was obtained. The scar was described in terms of its size (narrow or dehiscent) and its location in relation to the CIC (within or above), with each LUS scar classified into one of four groups based on these features. Placental location was assessed and classified as high- or low-lying. Women were stratified according to the risk of PAS, based on the relationship between the scar location and placental site. Women were considered high risk when the scar was above the CIC and the placenta was low-lying (i.e. when the placenta was overlying an exposed scar) and low risk when the scar was within the CIC and/or the placenta was high. High-risk patients were followed up at 20 weeks and 28-30 weeks for the development of PAS. Maternal demographics, detailed obstetric history and obstetric outcome were collected. RESULTS: First-trimester transvaginal ultrasound was offered to 535 women with prior CS during the study period. A LUS scar was visualized in 79.9% (401/502) of those who agreed to undergo the examination. At this scan, the LUS scar was above the CIC in 9.0% (36/401) of women, but only 5.7% (23/401) additionally had a low-lying placenta overlying the scar. Of these 23 high-risk women, two were found to have PAS on the mid-trimester screening scan and one was noted to have placental adherence during evacuation following mid-trimester termination of pregnancy. On the first-trimester scan, 94.3% (378/401) of women were at low risk of PAS. This screening protocol yielded a positive likelihood ratio of 21.33 (95% CI, 13.02-34.96), sensitivity of 100% (95% CI, 29.24-100%), specificity of 95.31% (95% CI, 92.39-97.35%), positive predictive value of 16.7% (95% CI, 5.8-39.2%) and negative predictive value of 100% (95% CI, 98.4-100%). On multivariable regression analysis performed to identify confounding variables associated with a LUS scar above the CIC, only maternal body mass index ≥ 30 kg/m2 was significant (odds ratio (OR), 2.42 (95% CI, 1.04-5.39); P = 0.03). Although there was a trend towards an increased risk of a LUS scar above the CIC in women with prior elective prelabor CS (OR, 1.72 (95% CI, 0.80-3.68)), this association did not reach statistical significance. CONCLUSIONS: Routine transvaginal ultrasound assessment of the location of the LUS scar and placenta at the time of first-trimester screening between 11 + 0 and 13 + 6 weeks' gestation in women with prior CS is a feasible and effective tool to identify those at risk of subsequent development of PAS disorder. A finding of placental implantation over an exposed LUS scar seems to be cardinal in predicting the risk of PAS disorder in women with prior CS, with an excellent negative predictive value. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

ISUOG Practice Guidelines: ultrasound assessment of fetal biometry and growth.

INTRODUCTION These Guidelines aim to describe appropriate assessment of fetal biometry and diagnosis of fetal growth disorders. These disorders consist mainly of fetal growth restriction (FGR), also referred to as intrauterine growth restriction (IUGR) and often associated with small­for­gestational age (SGA), and large­for­gestational age (LGA), which may lead to fetal macrosomia; both have been associated with a variety of adverse maternal and perinatal outcomes. Screening for, and adequate management of, fetal growth abnormalities are essential components of antenatal care, and fetal ultrasound plays a key role in assessment of these conditions. The fetal biometric parameters measured most commonly are biparietal diameter (BPD), head circumference (HC), abdominal circumference (AC) and femur diaphysis length (FL). These biometric measurements can be used to estimate fetal weight (EFW) using various different formulae1. It is important to differentiate between the concept of fetal size at a given timepoint and fetal growth, the latter being a dynamic process, the assessment of which requires at least two ultrasound scans separated in time. Maternal history and symptoms, amniotic fluid assessment and Doppler velocimetry can provide additional information that may be used to identify fetuses at risk of adverse pregnancy outcome. Accurate estimation of gestational age is a prerequisite for determining whether fetal size is appropriate­for­gestational age (AGA). Except for pregnancies arising from assisted reproductive technology, the date of conception cannot be determined precisely. Clinically, most pregnancies are dated by the last menstrual period, though this may sometimes be uncertain or unreliable. Therefore, dating pregnancies by early ultrasound examination at 8­14 weeks, based on measurement of the fetal crown­rump length (CRL), appears to be the most reliable method to establish gestational age. Once the CRL exceeds 84 mm, HC should be used for pregnancy dating2­4. HC, with or without FL, can be used for estimation of gestational age from the mid­trimester if a first­trimester scan is not available and the menstrual history is unreliable. When the expected delivery date has been established by an accurate early scan, subsequent scans should not be used to recalculate the gestational age1. Serial scans can be used to determine if interval growth has been normal. In these Guidelines, we assume that the gestational age is known and has been determined as described above, the pregnancy is singleton and the fetal anatomy is normal. Details of the grades of recommendation used in these Guidelines are given in Appendix 1. Reporting of levels of evidence is not applicable to these Guidelines.

Pautas de ISUOG para la práctica: evaluación ecográfica de la biometría y el crecimiento fetal INTRODUCCIÓN: El objetivo de estas Pautas es describir la evaluación adecuada de la biometría fetal y el diagnóstico de los trastornos del crecimiento fetal. Estos trastornos consisten principalmente en la restricción del crecimiento fetal (RCF), también conocida como restricción del crecimiento intrauterino (RCIU), que a menudo está asociada con un tamaño pequeño para la edad gestacional (PEG) o grande para la edad gestacional (GEG), que pueden dar lugar a la macrosomía fetal; ambos se han asociado con una variedad de resultados maternos y perinatales adversos. La detección y el tratamiento adecuado de las anomalías del crecimiento fetal son componentes esenciales de la atención prenatal, y la ecografía fetal desempeña un papel fundamental en la evaluación de estas afecciones. Los parámetros biométricos fetales medidos con mayor frecuencia son (todas las siglas procedentes del inglés) el diámetro biparietal (BPD), el perímetro cefálico (HC), el perímetro abdominal (AC) y la longitud de la diáfisis del fémur (FL). Estas mediciones biométricas se pueden utilizar para estimar el peso del feto (PEF) mediante fórmulas diferentes1 . Es importante diferenciar entre el concepto de tamaño fetal en un momento dado y el crecimiento fetal en sí, siendo este último un proceso dinámico cuya evaluación requiere al menos dos ecografías separadas en el tiempo. La historia y los síntomas de la madre, la evaluación del líquido amniótico y la velocimetría Doppler pueden proporcionar información adicional que se puede utilizar para identificar los fetos bajo riesgo de resultados adversos del embarazo. La estimación precisa de la edad gestacional es un prerrequisito para determinar si el tamaño del feto es apropiado para la edad gestacional (AEG). Excepto en el caso de los embarazos procedentes de tecnologías de reproducción asistida, la fecha de concepción no se puede determinar con precisión. Clínicamente, la fecha de la mayoría de los embarazos se establece en función del último período menstrual, aunque a veces esto puede ser incierto o poco fiable. Por lo tanto, el fechado de los embarazos mediante ecografía temprana a las 8-14 semanas, mediante la medición de la longitud céfalo-caudal (LCC) fetal, parece ser el método más fiable para establecer la edad gestacional. Una vez que la LCC excede los 84 mm, se debe usar el HC2-4 para establecer la fecha del embarazo. El HC, con o sin FL, se puede utilizar para estimar la edad gestacional a partir de la mitad del primer trimestre si no se dispone de una ecografía del primer trimestre y el historial menstrual no es fiable. Cuando se ha establecido la fecha prevista del parto mediante una exploración temprana precisa, no se deben utilizar exploraciones posteriores para recalcular la edad gestacional1 . Las exploraciones en serie se pueden utilizar para determinar si el intervalo del crecimiento ha sido normal. En estas Pautas se asume que la edad gestacional es conocida y ha sido determinada según lo anterior, que el embarazo es de feto único y que la anatomía fetal es normal. En el Apéndice 1 se detallan los grados de recomendación utilizados en estas Pautas. El informe sobre los niveles de evidencia no es aplicable a estas Pautas.

Evaluation of an objective method of image assessment for first-trimester nasal bone.

OBJECTIVE: To evaluate the degree of agreement in first-trimester nasal bone assessment in a group of sonographers before and after training, using a semi-quantitative scoring system. METHODS: Four sonographers who routinely perform first-trimester screening were first shown 46 images from both normal and trisomy 21 pregnancies. For each image, they were asked to score from 0 (disagree) to 3 (agree) on five different criteria that were deemed important in nasal-bone assessment, including image size, plane and visibility of nasal bone. A training program was then conducted, and a repeat exercise was carried out using the same 46 images. Finally, in a third exercise, images from 42 patients were presented, some having more than one image. The sonographers were required to give one overall nasal-bone score for each patient. In each exercise interobserver agreement was evaluated by intraclass correlation coefficient (ICC). RESULTS: Before training, the sonographers agreed reasonably well on the five proposed criteria (ICC, 0.752), with some disagreement on their perceived image quality. The training program further improved the agreement (ICC, 0.790), particularly on whether the nasal bone was the biggest and brightest echogenic component. Agreement was excellent when they were asked to give one overall score on the nasal bone based on multiple images from one patient (ICC, 0.929). CONCLUSION: The proposed scoring system can be used to improve consistency and reliability in first-trimester nasal-bone assessment.

Assessment of maternal anxiety levels before and after amniocentesis.

INTRODUCTION: To assess anxiety levels in mothers before and after undergoing amniocentesis. The secondary aim was to see how counselling by nurse-counsellors affected maternal anxiety levels. METHODS: A prospective study was carried out from February 2000 to August 2000 at the Kandang Kerbau Women's and Children's Hospital in Singapore. We used standard statistical analysis and Spielberger's state-trait anxiety inventory (STAI), that consisted of 40 items, to assess anxiety levels. Anxiety levels were assessed at different stages: before and after counselling; before amniocentesis and after amniocentesis; when results were disclosed; and after the routine 20-week screening ultrasound scan was acknowledged four to six weeks later. English-speaking women were recruited for the study as the STAI questionnaire has only been validated for an English-speaking population. 195 at-risk mothers (advanced maternal age, abnormal nuchal translucency on ultrasound scan, previous abnormal baby and high-risk maternal serum screening results) and patients requesting for amniocentesis between 15 to 20 weeks gestation were recruited. RESULTS: 156 mothers agreed to amniocentesis. 38 mothers declined amniocentesis. S-anxiety levels declined significantly after counselling by trained nurse-counsellors in all mothers counselled. S-anxiety levels were highest and significantly higher compared to all other times just prior to amniocentesis despite counselling. Anxiety levels were the lowest and significantly lower compared to all other times at the last assessment stage. CONCLUSION: High level of anxiety prior to amniocentesis despite counselling is understandable due to the invasive nature of the procedure. There is no long-lasting post-procedural anxiety to the mother.

Stochastic models for systems of interacting ion channels.

We consider a variety of Markov based models for systems of ion channels exhibiting dependence between channels. It is shown how many useful properties which may be calculated for an aggregated single-channel model, or a system of independent channels, can be extended to various types of interacting channel systems. Key structure and results from the theory of aggregated Markov processes are summarized in a convenient matrix form. These are then applied to the superposition of independent and dependent channels, including a patch of channels in a random environment, and a system of channels with spatial interactions. Calculations based on the resultant matrix expressions and intensity arguments can be implemented straightforwardly in a matrix-oriented package such as Matlab. The role of reversibility is also studied. A number of examples illustrate the strengths of the methods and enable numerical comparisons between the different types of systems.

Burst properties of a supergated double-barrelled chloride ion channel.

The chloride selective channel from Torpedo electroplax, ClC-0, is the prototype of a large gene family of chloride channels that behave as functional dimers, with channel currents exhibiting two non-zero conductance levels. Each pore has the same conductance and is controlled by a subgate, and these have seemingly identical fast gating kinetics. However, in addition to the two subgates there is a single slower 'supergate' which simultaneously affects both channels. In the present paper, we consider a six state Markov model that is compatible with these observations and develop approximations as well as exact results for relevant properties of groupings of openings, known as bursts. Calculations with kinetic parameter values typical of ClC-0 suggest that even simple approximations can be quite accurate. Small deviations from the assumption of independence within the model lead to marked changes in certain predicted burst properties. This suggests that analysis of these properties may be helpful in assessing independence/non-independence of gating in this type of channel. Based on simulations of models of both independent and non-independent gating, tests using binomial distributions can lead to false conclusions in each situation. This is made more problematic by the difficulty of selecting an appropriate critical time in defining a burst empirically.

Markov modeling of allosteric drug effects on ion channels, with particular reference to neuronal nicotinic acetylcholine receptors.

Allosteric mechanisms have been suggested for an increasing number of ion channel drug interactions, but often these ideas are not examined quantitatively through use of Markov models that would allow statistical estimation of proposed coupling effects. In this paper we illustrate, using properties relevant to the neuronal nicotinic acetylcholine receptor, how these models can be used to provide insight into the behavior of cooperative systems. Such models would then provide the basis for inferential studies with experimental data aimed at quantifying the magnitude of drug-induced changes on particular channel parameters. It is shown that even small changes in agonist binding affinity or channel gating are sufficient to produce biphasic modulatory drug effects in an allosteric model of nicotinic receptor activity.

Modulatory drug action in an allosteric Markov model of ion channel behaviour: biphasic effects with access-limited binding to either a stimulatory or an inhibitory site.

Concentration-dependent biphasic effects of drugs on ion channel activity have been reported in a variety of preparations, usually with stimulatory effects seen at low concentrations followed by increasingly dominant inhibition at higher levels. Such behaviour is often interpreted as evidence for the existence of separate modulatory drug binding sites. We demonstrate in this paper that it is possible for biphasic effects to be produced in an allosteric model of a ligand-activated ion channel, where diffusion-limited binding of the modulatory drug is restricted to either a stimulatory or an inhibitory site (but not both) because of steric overlap. The possibility of such an interaction mechanism should be kept in mind when interpreting experimental data if stoichiometric evidence from complementary techniques suggests that only one drug molecule is bound per receptor/ion channel complex.

Superposition properties of interacting ion channels.

Quantitative analysis of patch clamp data is widely based on stochastic models of single-channel kinetics. Membrane patches often contain more than one active channel of a given type, and it is usually assumed that these behave independently in order to interpret the record and infer individual channel properties. However, recent studies suggest there are significant channel interactions in some systems. We examine a model of dependence in a system of two identical channels, each modeled by a continuous-time Markov chain in which specified transition rates are dependent on the conductance state of the other channel, changing instantaneously when the other channel opens or closes. Each channel then has, e.g., a closed time density that is conditional on the other channel being open or closed, these being identical under independence. We relate the two densities by a convolution function that embodies information about, and serves to quantify, dependence in the closed class. Distributions of observable (superposition) sojourn times are given in terms of these conditional densities. The behavior of two channel systems based on two- and three-state Markov models is examined by simulation. Optimized fitting of simulated data using reasonable parameters values and sample size indicates that both positive and negative cooperativity can be distinguished from independence.

Model properties underlying non-identifiability in single channel inference.

Models of ion channel kinetics subserve inferential methods applied to patch clamp data. For Markov models the density function of a sojourn time in a class of states is a mixture of exponentials. Determination of kinetic parameters from density functions may be complicated by non-uniqueness of solutions. This non-identifiability is investigated analytically for a class of two states, assuming detailed balance; relations between model properties, observable density parameters, and non-uniqueness are presented. The results are further developed in terms of similarity transform methods. Additional information provided by joint distributions is discussed. An example is given where identifiability of a model can be demonstrated explicitly. Attention is drawn to instances where the number of components in a density function may be misleading when used to infer the number of underlying states.

Single ion channel models incorporating aggregation and time interval omission.

We present a general theoretical framework, incorporating both aggregation of states into classes and time interval omission, for stochastic modeling of the dynamic aspects of single channel behavior. Our semi-Markov models subsume the standard continuous-time Markov models, diffusion models and fractal models. In particular our models allow for quite general distributions of state sojourn times and arbitrary correlations between successive sojourn times. Another key feature is the invariance of our framework with respect to time interval omission: that is, properties of the aggregated process incorporating time interval omission can be derived directly from corresponding properties of the process without it. Even in the special case when the underlying process is Markov, this leads to considerable clarification of the effects of time interval omission. Among the properties considered are equilibrium behavior, sojourn time distributions and their moments, and auto-correlation and cross-correlation functions. The theory is motivated by ion channel mechanisms drawn from the literature, and illustrated by numerical examples based on these.

Graphs, random sums, and sojourn time distributions, with application to ion-channel modeling.

This paper considers the distribution of a sojourn time in a class of states of a stochastic process having finite discrete state space where sojourn times in any individual state are independent and identically distributed, and transitions between states follow a Markov chain. The state space and possible transitions of the process are represented by a graph. Class sojourn time distributions are derived by modifying this graph using 'composition' of states, defining a new Markov chain on the modified graph, and expressing the sojourn time in a composition state as a random sum. Appropriate compositions are chosen according to the possible "cores" of sojourns in the particular class, where a core describes the structure of a sojourn in terms of a single state or a chain in the original graph. Graph methods provide an algorithmic basis for the derivation, which can be simplified by using symmetry results. Models of ion-channel kinetics are used throughout for illustration; class sojourn time distributions are important in such models because individual states are often indistinguishable experimentally. Markov processes are the special case where sojourn times in individual states are exponentially distributed. In this case kinetic parameter estimation based on the observed class sojourn time distribution is briefly discussed; explicit estimating equations applicable to sequential models of nicotinic receptor kinetics are given.

Statistical inference from single channel records: two-state Markov model with limited time resolution.

Though stochastic models are widely used to describe single ion channel behaviour, statistical inference based on them has received little consideration. This paper describes techniques of statistical inference, in particular likelihood methods, suitable for Markov models incorporating limited time resolution by means of a discrete detection limit. To simplify the analysis, attention is restricted to two-state models, although the methods have more general applicability. Non-uniqueness of the mean open-time and mean closed-time estimators obtained by moment methods based on single exponential approximations to the apparent open-time and apparent closed-time distributions has been reported. The present study clarifies and extends this previous work by proving that, for such approximations, the likelihood equations as well as the moment equations (usually) have multiple solutions. Such non-uniqueness corresponds to non-identifiability of the statistical model for the apparent quantities. By contrast, higher-order approximations yield theoretically identifiable models. Likelihood-based estimation procedures are developed for both single exponential and bi-exponential approximations. The methods and results are illustrated by numerical examples based on literature and simulated data, with consideration given to empirical distributions and model control, likelihood plots, and point estimation and confidence regions.

Stochastic modelling of a single ion channel: an alternating renewal approach with application to limited time resolution.

Stochastic models of ion channels have been based largely on Markov theory where individual states and transition rates must be specified, and sojourn-time densities for each state are constrained to be exponential. This study presents an approach based on random-sum methods and alternating-renewal theory, allowing individual states to be grouped into classes provided the successive sojourn times in a given class are independent and identically distributed. Under these conditions Markov models form a special case. The utility of the approach is illustrated by considering the effects of limited time resolution (modelled by using a discrete detection limit, xi) on the properties of observable events, with emphasis on the observed open-time (xi-open-time). The cumulants and Laplace transform for a xi-open-time are derived for a range of Markov and non-Markov models; several useful approximations to the xi-open-time density function are presented. Numerical studies show that the effects of limited time resolution can be extreme, and also highlight the relative importance of the various model parameters. The theory could form a basis for future inferential studies in which parameter estimation takes account of limited time resolution in single channel records. Appendixes include relevant results concerning random sums and a discussion of the role of exponential distributions in Markov models.