Implementation of maternal blood cell-free DNA testing in early screening for aneuploidies.

Several externally blinded validation and implementation studies in the last 9 years have shown that it is now possible, through analysis of cell-free (cf) DNA in maternal blood, to effectively detect a high proportion of fetuses affected by trisomies 21, 18, and 13 at a much lower false-positive rate (FPR) than all other existing screening methods. This article is aimed at reviewing technical and clinical considerations for implementing cfDNA testing in routine practice, including methods of analysis, performance of the test, models for clinical implementation, and interpretation of results.post-print305 K

Intelligent Noninvasive Diagnosis of Aneuploidy:Raw Values and Highly Imbalanced Dataset

The objective of this paper is to introduce a noninvasive diagnosis procedure for aneuploidy and to minimize the social and financial cost of prenatal diagnosis tests that are performed for fetal aneuploidies in an early stage of pregnancy. We propose a method by using artificial neural networks trained with data from singleton pregnancy cases, while undergoing first trimester screening. Three different datasets' with a total of 122 362 euploid and 967 aneuploid cases were used in this study. The data for each case contained markers collected from the mother and the fetus. This study, unlike previous studies published by the authors for a similar problem differs in three basic principles: 1) the training of the artificial neural networks is done by using the markers' values in their raw form (unprocessed), 2) a balanced training dataset is created and used by selecting only a representative number of euploids for the training phase, and 3) emphasis is given to the financials and suggest hierarchy and necessity of the available tests. The proposed artificial neural networks models were optimized in the sense of reaching a minimum false positive rate and at the same time securing a 100% detection rate for Trisomy 21. These systems correctly identify other aneuploidies (Trisomies 13&18, Turner, and Triploid syndromes) at a detection rate greater than 80%. In conclusion, we demonstrate that artificial neural network systems can contribute in providing noninvasive, effective early screening for fetal aneuploidies with results that compare favorably to other existing methods

Preterm and term pre-eclampsia: relative burdens of maternal and perinatal complications.

To determine the relative burdens of maternal and perinatal complications, for preterm and term pre-eclampsia. Prospective observational cohort study. Two English maternity units. Unselected women with singleton pregnancies who developed pre-eclampsia (International Society for the Study of Hypertension in Pregnancy definition). Outcomes were ascertained by health record review and compared between pregnancies with preterm (vs. term) pre-eclampsia. Severe maternal hypertension, maternal mortality or major maternal morbidity, perinatal mortality or major neonatal morbidity, neonatal unit (NNU) admission ≥48 hours, and birthweight <3 percentile. Among 40,241 singleton pregnancies, 298 (0.7% [95% confidence interval 0.66-0.83]) and 1194 (3.0% [2.8-3.1]) developed preterm and term pre-eclampsia, respectively. Women with preterm (vs term) pre-eclampsia more commonly experienced adverse maternal or perinatal events (severe hypertension: 18.5% [14.5-23.3] vs 13.6% [11.7-15.6]; maternal mortality/major morbidity: 7.4% [4.9-10.9] vs 2.2% [1.5-3.2]; perinatal mortality/major neonatal morbidity: 29.5% [24.6-34.9] vs 2.2% [1.5-3.2]; and birthweight <3 percentile: 54.4% [48.7-59.9] vs 14.2% [12.4-16.3]). However, in absolute terms, most maternal complications occurred in women with term pre-eclampsia, as did a large proportion of perinatal complications: severe hypertension (74.7% [68.5-80.0]); maternal mortality/major morbidity (54.2% [40.3-67.4]), perinatal mortality/major neonatal morbidity (22.8% [16.1-31.3]); NNU admission ≥48 hours (38.1% [32.4-44.1]); and birthweight <3 percentile (51.2% [45.8-56.5]). While adverse event risks are greater with preterm (vs term) pre-eclampsia, term disease is associated with at least equivalent total numbers of maternal, and a significant proportion of perinatal, adverse events. Increased efforts should be made to decrease the incidence of term pre-eclampsia. [Abstract copyright: This article is protected by copyright. All rights reserved.

A multimodality navigation system for endoscopic fetal surgery : a phantom case study for congenital diaphragmatic hernia

This article presents a multi-modality tracking and navigation system achieved by merging optical tracking and ultrasound imaging into a novel navigation software to help in surgical pre-planning and real-time target setting and guidance. Fetal surgeries require extensive experience in coordination of hand-eye-ultrasound-surgical equipment, knowledge, and precise assessment of relative anatomy. While there are navigation systems available for similar constrained working spaces in arthroscopic and cardiovascular procedures, fetal minimally invasive surgery does not yet have a dedicated navigation platform capable of supporting robotic instruments that can be adapted to the set of unique procedures. This article discusses the testing of the novel multi-modality navigation system in a phantom environment developed for this purpose. The outcomes suggest that the subjects demonstrated an increase in average reaching accuracy by about 60% and an overall reduction in time taken by 33.6%. They also showed higher levels of confidence in reaching the targets, which was visualised from the pattern of trajectory of movements during the procedure. To evaluate the navigation system, a phantom surgical environment was found necessary. Therefore, the article also discusses the details of the development of a fetal phantom environment for congenital diaphragmatic hernia for surgical testing, evaluation, and training. A surgical procedure was conducted on the phantom using the proposed tracking navigation system and using only ultrasound

Maternal serum concentrations of pregnancy associated placental protein A and pregnancy specific β-1-glycoprotein in multifetal pregnancies before and after fetal reduction

Placental function in multifetal pregnancies before and after embryo reduction was investigated by measuring maternal serum concentrations of pregnancy associated placental protein-A (PAPP-A) and pregnancy specific β-1-glycoprotein (SP-1). Three groups of pregnant women were studied following assisted reproduction; groups 1 and 2, were 12 singleton and 12 twin pregnancies respectively, and group 3 comprised 12 women with multifetal pregnancies undergoing embryo reduction. PAPP-A and SP-1 were measured serially at 8-21 weeks gestation. In all pregnancies, maternal serum PAPP-A and SP-1 increased with gestation. In twin pregnancies the mean concentrations of SP-1 were significantly higher than in singletons at all gestations, whereas for PAPP-A, concentrations were similar between these groups. In multifetal pregnancies before embryo reduction, the serum concentrations of both proteins were significantly higher than in twin pregnancies. Following reduction, the concentrations of PAPP-A remained significantly higher than for twins throughout, whereas the concentrations of SP-1 gradually converged towards those of twins; by 19 weeks there was no difference between the means of the two groups. These findings suggest that circulating concentrations of SP-1 reflect total placenta mass, which is proportional to the number of live fetuses, whereas the pattern of PAPP-A changes suggests that this protein is produced by the placenta, decidua and other tissue

First-trimester screening for trisomies by cfDNA testing of maternal blood in singleton and twin pregnancies: factors affecting test failure.

Objectives: To examine factors affecting the failure rate to obtain a result from (cf) DNA testing of maternal blood for fetal trisomies 21, 18 and 13 in singleton and twin pregnancies in the first trimester of pregnancy. Methods: This was a prospective study in 23,495 singleton and 928 twin pregnancies undergoing screening for fetal trisomies by targeted cfDNA testing at 10+0-14+1 weeks’ gestation. Multivariate regression analysis was used to determine significant predictors of failure to obtain a result after first sampling. Results: There was no result from cfDNA testing after first sampling in 3.4% (798/23,495) of singletons, 11.3% (91/806) of DC twins and in 4.9% (6/122) of MC twins. Multivariate logistic regression analysis demonstrated that the risk of test failure first, increased with increasing maternal age (odds ratio (OR) 1.02; 95% confidence interval (CI) 1.01, 1.04) and weight (OR 1.05; 95% CI 1.04, 1.05), decreasing gestational age (OR 0.85; 95% CI 0.79, 0.91) and serum PAPP-A (OR 0.56; 95% CI 0.49, 0.64) and free ß-hCG (OR 0.67; 95% CI 0.60, 0.74), second, was higher in women of Black (OR 1.72; 95% CI 1.33, 2.20) and South Asian (OR 1.99; 95% CI 1.56, 2.52) than White racial origin, in dichorionic twin (OR 1.75; 95% CI 1.34, 2.25) than singleton pregnancy and in in vitro fertilization (OR 3.82; 95% CI 3.19, 4.55) than natural conception and third, was lower in parous (OR 0.63; 95% CI 0.55, 0.74) than nulliparous women. Conclusions: Maternal age, weight, racial origin and parity, gestational age, dichorionicity, method of conception and serum levels of free ß-hCG and PAPP-A are independent predictors of cfDNA test failure. The risk of test failure is higher in dichorionic twin than in singleton pregnancies, mainly because a higher proportion of twins are conceived by in vitro fertilization and more of the women are nulliparous.pre-print429 K

Gestación gemelar monocorial con rciu selectivo tipo 2: Hallazgos ecográficos y fetoscópicos de mal pronóstico

A pregnant woman with monochorionic twins was referred to our Centre due to discrepancy in size between the twins. She was 17 weeks pregnant when we made the diagnosis of selective IUGR type 2 and we decided to perform a fetoscopic Laser ablation of the placental anastomoses. During the fetoscopy, we identified an arterio-venous anastomosis with bidirectional flux that is completely atypical in these anastomoses, never reported before, thus representing a sign of bad prognosis for the small twin.Presentamos el caso de una gestante de 17 semanas con una gestación gemelar monocoriónica biamniótica complicada con RCIU selectivo tipo 2 que requirió, de acuerdo a criterios ecográficos, ablación quirúrgica Láser de las anastomosis placentarias. Se identificó durante la fetoscopía una anastomosis arterio-venosa que mostraba flujo bidireccional lo cual es sumamente inusual en estas anastomosis, no reportado antes en la literatura, constituyendo un signo de mal pronóstico para el gemelo pequeño

First Trimester Noninvasive Prenatal Diagnosis:A Computational Intelligence Approach

The objective of this study is to examine the potential value of using machine learning techniques such as artificial neural network (ANN) schemes for the noninvasive estimation, at 11-13 weeks of gestation, the risk for euploidy, trisomy 21 (T21), and other chromosomal aneuploidies (O.C.A.), from suitable sonographic, biochemical markers, and other relevant data. A database(1) consisted of 51,208 singleton pregnancy cases, while undergoing first trimester screening for aneuploidies has been used for the building, training, and verification of the proposed method. From all the data collected for each case from the mother and the fetus, the following 9 are considered by the collaborating obstetricians as the most relevant to the problem in question: maternal age, previous pregnancy with T21, fetal crown-rump length, serum free beta-hCG in multiples of the median (MoM), pregnancy-associated plasma protein-A in MoM, nuchal translucency thickness, nasal bone, tricuspid flow, and ductus venosus flow. The dataset was randomly divided into a training set that was used to guide the development of various ANN schemes, support vector machines, and k-nearest neighbor models. An evaluation set used to determine the performance of the developed systems. The evaluation set, totally unknown to the proposed system, contained 16,898 cases of euploidy fetuses, 129 cases of T21, and 76 cases of O.C.A. The best results were obtained by the ANN system, which identified correctly all T21 cases, i.e., 0% false negative rate (FNR) and 96.1% of euploidies, i.e., 3.9% false positive rate (FPR), meaning that no child would have been born with T21 if only that 3.9% of all pregnancies had been sent for invasive testing. The aim of this work is to produce a practical tool for the obstetrician which will ideally provide 0% FNR and to recommend the minimum possible number of cases for further testing such as invasive. In conclusion, it was demonstrated that ANN schemes can provide an effective early screening for fetal aneuploidies at a low FPR with results that compare favorably to those of existing systems

A link between high serum levels of human chorionic gonadotrophin and chorionic expression of its mature functional receptor (LHCGR) in Down's syndrome pregnancies

Human chorionic gonadotrophin (hCG) is released from placental trophoblasts and is involved in establishing pregnancy by maintaining progesterone secretion from the corpus luteum. Serum hCG is detected in the maternal circulation within the first 2–3 wks of gestation and peaks at the end of the first trimester before declining. In Down's syndrome (DS) pregnancies, serum hCG remains significantly high compared to gestation age-matched uncompromised pregnancies. It has been proposed that increased serum hCG levels could be due to transcriptional hyper-activation of the CGB (hCG beta) gene, or an increased half life of glycosylated hCG hormone, or both. Another possibility is that serum hCG levels remain high due to reduced availability of the hormone's cognate receptor, LHCGR, leading to lack of hormone utilization. We have tested this hypothesis by quantifying the expression of the hCG beta (CGB) RNA, LHCGR RNA and LHCGR proteins in chorionic villous samples. We demonstrate that chorionic expression of hCG beta (CGB) mRNA directly correlates with high serum hCG levels. The steady-state synthesis of LHCGR mRNA (exons 1–5) in DS pregnancies was significantly higher than that of controls, but the expression of full-length LHCGR mRNA (exons 1–11) in DS was comparable to that of uncompromised pregnancies. However, the synthesis of high molecular weight mature LHCGR proteins was significantly reduced in DS compared to uncompromised pregnancies, suggesting a lack of utilization of circulating hCG in DS pregnancies

Glucose metabolism in pregnancy at high altitude

WSTĘP. Celem badania była ocena wrażliwości na insulinę oraz funkcji komórek b związanych z niższą glikemią na czczo u kobiet ciężarnych przebywających na dużych wysokościach w porównaniu z ciężarnymi mieszkającymi na poziomie morza. MATERIAŁ I METODY. W badaniu uczestniczyło 215 kobiet w 8-42 tygodniu ciąży, mieszkających w Peru. Rekrutację przeprowadzono w miejscowościach Cerro de Pasco, która znajduje się 4370 m (14 340 stóp) nad poziomem morza, oraz w Limie, leżącej na wysokości poziomu morza. Grupę kontrolną stanowiły 53 kobiety, które nie były w ciąży (22 w Cerro de Pasco i 31 w Limie). Glikemię, insulinemię oraz stężenie C-peptydu i proinsuliny na czczo zmierzono w próbkach krwi uzyskanych z żyły odłokciowej w godzinach 8.00&#8211;10.00, wcześniej pacjentki nie przyjmowały pokarmów przez 10&#8211;14 godzin. Insulinooporność oraz funkcje komórek b obliczono z zastosowaniem modelu oceny homeostazy. WYNIKI. Stężenie C-peptydu na czczo oraz funkcja komórek b były podobne, stężenie insuliny oraz proinsuliny na czczo były niższe, natomiast insulinooporność była wyższa u kobiet przebywających na większej wysokości. WNIOSKI. Niższa glikemia na czczo u kobiet ciężarnych przebywających na obszarach położonych wyżej w porównaniu z ciężarnymi zamieszkującymi na poziomie morza przy podobnym wydzielaniu insuliny wiąże się z większą obwodową wrażliwością na insulinę. Zjawisko to może częściowo tłumaczyć niższą masę urodzeniową dzieci matek z obszarów położonych wysoko nad poziomem morza.OBJECTIVE. To assess insulin sensitivity and b-cell function associated with lower maternal fasting plasma glucose levels at high altitude compared with sea level. RESEARCH DESIGN AND METHODS. We studied 215 pregnant women at 8&#150;42 weeks of gestation in Peru. The women were recruited from Cerro de Pasco, which is situated 4,370 m (14,340 feet) above sea level, and Lima, which is at sea level. We also examined 53 nonpregnant control subjects (22 in Cerro de Pasco and 31 in Lima). Fasting plasma glucose, insulin, C-peptide, and proinsulin concentrations were measured in samples obtained from the antecubital vein between 8:00 A.M. and 10:00 A.M. after an overnight period of fasting for 10&#150;14 h. Insulin resistance and b-cell function were calculated using homeostasis model assessment. RESULTS. Fasting C-peptide levels and b-cell function were similar, fasting concentrations of insulin and proinsulin were lower, and insulin sensitivity was higher at high altitude compared with sea level. CONCLUSIONS. Maternal fasting plasma glucose that is lower at high altitude than at sea level in the presence of similar insulin secretion is associated with higher peripheral insulin sensitivity. This may partly explain the lower birth weights at high altitudes