ObjectiveAccurate individualized assessment of preeclampsia risk enables the identification of patients most likely to benefit from initiation of low-dose aspirin at 12-16 weeks’ gestation when there is evidence for its effectiveness, as well as guiding appropriate pregnancy care pathways and surveillance. The primary objective of this study was to evaluate the performance of artificial neural network models for the prediction of preterm preeclampsia (<37 weeks’ gestation) using patient characteristics available at the first antenatal visit and data from prenatal cell-free DNA (cfDNA) screening. Secondary outcomes were prediction of early onset preeclampsia (<34 weeks’ gestation) and term preeclampsia (≥37 weeks’ gestation).MethodsThis secondary analysis of a prospective, multicenter, observational prenatal cfDNA screening study (SMART) included singleton pregnancies with known pregnancy outcomes. Thirteen patient characteristics that are routinely collected at the first prenatal visit and two characteristics of cfDNA, total cfDNA and fetal fraction (FF), were used to develop predictive models for early-onset (<34 weeks), preterm (<37 weeks), and term (≥37 weeks) preeclampsia. For the models, the ‘reference’ classifier was a shallow logistic regression (LR) model. We also explored several feedforward (non-linear) neural network (NN) architectures with one or more hidden layers and compared their performance with the LR model. We selected a simple NN model built with one hidden layer and made up of 15 units.ResultsOf 17,520 participants included in the final analysis, 72 (0.4%) developed early onset, 251 (1.4%) preterm, and 420 (2.4%) term preeclampsia. Median gestational age at cfDNA measurement was 12.6 weeks and 2,155 (12.3%) had their cfDNA measurement at 16 weeks’ gestation or greater. Preeclampsia was associated with higher total cfDNA (median 362.3 versus 339.0 copies/ml cfDNA; p<0.001) and lower FF (median 7.5% versus 9.4%; p<0.001). The expected, cross-validated area under the curve (AUC) scores for early onset, preterm, and term preeclampsia were 0.782, 0.801, and 0.712, respectively for the LR model, and 0.797, 0.800, and 0.713, respectively for the NN model. At a screen-positive rate of 15%, sensitivity for preterm preeclampsia was 58.4% (95% CI 0.569, 0.599) for the LR model and 59.3% (95% CI 0.578, 0.608) for the NN model.The contribution of both total cfDNA and FF to the prediction of term and preterm preeclampsia was negligible. For early-onset preeclampsia, removal of the total cfDNA and FF features from the NN model was associated with a 6.9% decrease in sensitivity at a 15% screen positive rate, from 54.9% (95% CI 52.9-56.9) to 48.0% (95% CI 45.0-51.0).ConclusionRoutinely available patient characteristics and cfDNA markers can be used to predict preeclampsia with performance comparable to other patient characteristic models for the prediction of preterm preeclampsia. Both LR and NN models showed similar performance.

ABSTRACT Although cell-free DNA (cfDNA) prenatal screening is widely used and has high sensitivity and specificity, there are circumstances in which the screening does not provide an interpretable result. Although this is relatively uncommon, it happens enough that clinical implications and potential reasons for follow-up should be studied and assessed. This study was designed to evaluate outcomes for pregnancies with nonreportable results on cfDNA screening tests. This study was a secondary analysis of the data from a multicenter prospective observational study of cfDNA screening for aneuploidy and 22q11.2 deletion syndrome. All patients were tested for trisomies 13, 18, and 21, as well as the 22q11.2 deletion syndrome, and all patients had confirmatory testing on the newborns in addition to collecting obstetric and perinatal outcomes. Inclusion criteria were women older than 18 years and at greater than 9 weeks of gestation with a singleton pregnancy. Exclusion criteria were having received cfDNA screening results before enrollment, organ transplant, ovum donation, vanishing twin, or being unwilling to provide a newborn sample. The primary outcome was the rate of adverse obstetrical and perinatal outcomes, including aneuploidy; preterm birth at less than 28, 34, or 37 weeks' gestation; preeclampsia; small for gestational age birth; and a composite outcome that included preterm birth before 37 weeks, preeclampsia, stillbirth at greater than 20 weeks, and small for gestational age. Final analyses included 17,851 individuals who had cfDNA screening, confirmatory genetic testing on the newborn, and obstetrical and perinatal outcomes recorded. Nonreportable results were found in 602 individuals (3.4%) after the first draw, with 32.2% of these due to low fetal fraction. Another third of the cohort had patterns where the risk of aneuploidy was uninterpretable but with an adequate fetal fraction, and in the final third, the fetal fraction could not be measured. Of the original 602 cases of nonreportable findings, 427 had a second draw, with 112 of these (26.2%) again having nonreportable results. There were no significant differences in baseline characteristics of age and parity for those with successful versus nonreportable test results; gestational age was significantly higher in individuals with nonreportable results (14.4 vs 13.4 weeks, P < 0.001), as was body mass index (26.2 vs 31.3), and the rate of chronic hypertension (4.0% vs 9.7%). In this cohort, there were 133 genetically confirmed trisomies, with 100 fetuses with trisomy 21, 18 individuals with trisomy 18, and 15 individuals with trisomy 13. Overall, the rate of aneuploidy was 1.7% in individuals with nonreportable results, versus 0.7% in those with reported results (P = 0.013; adjusted odds ratio [aOR] 2.1; 95% confidence interval [CI], 1.1–4.0). Rates of preterm birth were also higher in those with nonreportable test results, with delivery at less than 34 weeks at 1.5% in those with a test result, 4.6% in those with one nonreportable test result and 6.9% in those with a second nonreportable test result (aOR, 2.2 and 2.7; 95% CI, 1.4–3.4 and 1.2–6.0, respectively). Preeclampsia showed a similar trend, with rates climbing from 3.9% in those with a reported result to 9.4% with 1 nonreportable result and 16.8% with 2 (aOR, 1.4 and 2.0; 95% CI, 1.0–1.9 and 1.1–3.7, respectively). Chances of live birth were significantly reduced in pregnancies with a nonreportable results (aOR, 0.20; 95% CI, 0.13–0.30), with the chances decreasing more after a second nonreportable test result (aOR, 0.11; 95% CI, 0.06–0.23). The study found that nonreportable cfDNA screening results are associated with an increased risk for aneuploidy, preterm birth, and preeclampsia, with a gradient of increased risk with a second failed test. This adds to literature with conflicting findings surrounding obstetrical complications in those with altered cfDNA levels and with most studies largely focused on characteristics that may be predictive of a nonreportable result rather than outcomes associated with nonreportable results. These results can inform clinicians who have patients with nonreportable test results in a way that may help them provide better care; future research should focus on more fully understanding the adverse outcomes associated with nonreportable tests to maximize this ability for clinicians in the future. Further research should also focus on specific populations or diagnoses to understand if there are fundamental differences in different groups of individuals.

PURPOSE:The aim of this study was to assess the performance of cell-free DNA (cfDNA) screening to detect sex chromosome aneuploidies (SCAs) in an unselected obstetrical population with genetic confirmation.METHODS:This was a planned secondary analysis of the multicenter, prospective SNP-based Microdeletion and Aneuploidy RegisTry (SMART) study. Patients receiving cfDNA results for autosomal aneuploidies and who had confirmatory genetic results for the relevant sex chromosomal aneuploidies were included. Screening performance for SCAs, including monosomy X (MX) and the sex chromosome trisomies (SCT: 47,XXX; 47,XXY; 47,XYY) was determined. Fetal sex concordance between cfDNA and genetic screening was also evaluated in euploid pregnancies.RESULTS:A total of 17,538 cases met inclusion criteria. Performance of cfDNA for MX, SCTs, and fetal sex was determined in 17,297, 10,333, and 14,486 pregnancies, respectively. Sensitivity, specificity, and positive predictive value (PPV) of cfDNA were 83.3%, 99.9%, and 22.7% for MX and 70.4%, 99.9%, and 82.6%, respectively, for the combined SCTs. The accuracy of fetal sex prediction by cfDNA was 100%.CONCLUSION:Screening performance of cfDNA for SCAs is comparable to that reported in other studies. The PPV for the SCTs was similar to the autosomal trisomies, whereas the PPV for MX was substantially lower. No discordance in fetal sex was observed between cfDNA and postnatal genetic screening in euploid pregnancies. These data will assist interpretation and counseling for cfDNA results for sex chromosomes.

ObjectivesTo assess brain development in living fetuses with Down syndrome (DS) by biometric measurements on fetal brain magnetic resonance images (MRI).MethodsWe scanned 10 MRIs of fetuses with confirmed trisomy 21 at birth and 12 control fetal MRIs without any detected anomalies. Fetal brain MRIs were analyzed using 14 fetal brain and skull biometric parameters. We compared measures between DS and controls in both raw MRIs and motion-corrected and anterior-posterior commissure-aligned images.ResultsIn the reconstructed images, the measured values of the height of the cerebellar vermis (HV) and anteroposterior diameter of the cerebellar vermis (APDV) were significantly smaller, and the anteroposterior diameter of the fourth ventricle (APDF) was significantly larger in fetuses with DS than controls. In the raw MRIs, the measured values of the right lateral ventricle were significantly larger in fetuses with DS than in controls. Logistic regression analyses revealed that a new parameter, the cerebellar-to-fourth-ventricle ratio (i.e., (APDV * Height of the vermis)/APDF), was significantly smaller in fetuses with DS than controls and was the most predictive to distinguish between fetuses with DS and controls.ConclusionsThe study revealed that fetuses with DS have smaller cerebellums and larger fourth ventricles compared to the controls. What is already known about this topic?The understanding of the anatomical brain abnormalities in Down syndrome (DS) has come mostly from fetal autopsies, demonstrated by a grossly reduced brain weight.Knowledge from living fetuses with DS is scarce and comes mainly from sonographic analyses.Biometric MRI measurement is gaining widespread acceptance to evaluate fetal brain development.What does this study add?Our biometric measures revealed that fetuses with DS have smaller cerebellums and larger fourth ventricles compared with controls.Smaller cerebellar-to-fourth-ventricle ratios may be a novel fetal brain feature that is characteristic of DS.

OBJECTIVE:One goal of prenatal genetic screening is to optimize perinatal care and improve infant outcomes. We sought to determine whether high-risk cfDNA screening for 22q11.2 deletion syndrome (22q11.2DS) affected prenatal or neonatal management. METHODS:This was a secondary analysis from the SMART study. Patients with high-risk cfDNA results for 22q11.2DS were compared with the low-risk cohort for pregnancy characteristics and obstetrical management. To assess differences in neonatal care, we compared high-risk neonates without prenatal genetic confirmation with a 1:1 matched low-risk cohort. RESULTS:Of 18,020 eligible participants enrolled between 2015 and 2019, 38 (0.21%) were high-risk and 17,982 (99.79%) were low-risk for 22q11.2DS by cfDNA screening. High-risk participants had more prenatal diagnostic testing (55.3%; 21/38 vs. 2.0%; 352/17,982, p < 0.001) and fetal echocardiography (76.9%; 10/13 vs. 19.6%; 10/51, p < 0.001). High-risk newborns without prenatal diagnostic testing had higher rates of neonatal genetic testing (46.2%; 6/13 vs. 0%; 0/51, P < 0.001), echocardiography (30.8%; 4/13 vs. 4.0%; 2/50, p = 0.013), evaluation of calcium levels (46.2%; 6/13 vs. 4.1%; 2/49, P < 0.001) and lymphocyte count (53.8%; 7/13 vs. 15.7%; 8/51, p = 0.008). CONCLUSIONS:High-risk screening results for 22q11.2DS were associated with higher rates of prenatal and neonatal diagnostic genetic testing and other 22q11.2DS-specific evaluations. However, these interventions were not universally performed, and >50% of high-risk infants were discharged without genetic testing, representing possible missed opportunities to improve outcomes for affected individuals.

Non-invasive prenatal screening with cell free DNA (cfDNA) includes the option to screen for microdeletion syndromes but data on test performance are limited. We report on performance of cfDNA for detection of 4 microdeletion syndromes: Cri-Du-Chat (5p-), Prader-Willi syndrome (PWS), Angelman syndrome (AS) and 1p36del syndrome. Secondary analysis of the SMART multicenter prospective study, which assessed cfDNA performance for 22q11.2 deletion. Newborn or fetal samples were requested in all cases for genetic confirmation with chromosomal microarray (CMA). SNP-based cfDNA screening for 4 microdeletion syndromes was performed using an investigational algorithm on patients who requested testing for these syndromes or who agreed to future research; results were compared to blinded CMA confirmation. Differentiation between PWS and AS, caused by a similar deletion/imprinting mechanism, was accomplished by comparing neonatal SNPs on CMA and maternal SNPs, if available from the cfDNA sample, in the affected region. Deletions >500kb in the syndrome critical region were considered positive. Deletions < 500kb or not including the disease-causing genes were classified as variants of uncertain significance (VUS). Overall, 10,971 had both cfDNA and DNA confirmation results. Median gestational age at enrollment was 13.3 weeks (8.9–36.1). CMA confirmed 5 PWS cases (1:2194), one case of PWS/AS and one 5p- (Table). Four 5p- deletions and one 1p36del were classified as VUS. Of the 7 confirmed microdeletion cases, 6 were detected by cfDNA (86.7%), including all PWS/AS cases; the 5p- case was not detected. cfDNA was reported as high-risk in 14 cases (0.12%), with FP=0.07%, a PPV of 62.5% (5/8) for PWS, and 0% (0/6) for the remaining 3 conditions. None of the confirmed cases had increased NT or structural anomalies at the time of the anatomic survey. One PWS case was diagnosed with fetal anomalies at 32wks and 2 PWS cases were diagnosed with abnormalities after birth. cfDNA prenatal screening detected 6/7 microdeletions, including all cases of PWS/AS, with a low false positive rate.

BACKGROUND: Cell-free DNA noninvasive prenatal screening for trisomies 21, 18, and 13 has been rapidly adopted into clinical practice. However, previous studies are limited by a lack of follow-up genetic testing to confirm the outcomes and accurately assess test performance, particularly in women at a low risk for aneuploidy. OBJECTIVE: To measure and compare the performance of cell-free DNA screening for trisomies 21, 18, and 13 between women at a low and high risk for aneuploidy in a large, prospective cohort with genetic confirmation of results STUDY DESIGN: This was a multicenter prospective observational study at 21 centers in 6 countries. Women who had single-nucleotide-polymorphism-based cell-free DNA screening for trisomies 21, 18, and 13 were enrolled. Genetic confirmation was obtained from prenatal or newborn DNA samples. The test performance and test failure (no-call) rates were assessed for the cohort, and women with low and high previous risks for aneuploidy were compared. An updated cell-free DNA algorithm blinded to the pregnancy outcome was also assessed. RESULTS: A total of 20,194 women were enrolled at a median gestational age of 12.6 weeks (interquartile range, 11.6-13.9). The genetic outcomes were confirmed in 17,851 cases (88.4%): 13,043 (73.1%) low-risk and 4808 (26.9%) high-risk cases for aneuploidy. Overall, 133 trisomies were diagnosed (100 trisomy 21; 18 trisomy 18; 15 trisomy 13). The cell-free DNA screen positive rate was lower in the low-risk vs the high-risk group (0.27% vs 2.2%; P<.0001). The sensitivity and specificity were similar between the groups. The positive predictive value for the low- and high-risk groups was 85.7% vs 97.5%; P=.058 for trisomy 21; 50.0% vs 81.3%; P=.283 for trisomy 18; and 62.5% vs 83.3; P=.58 for trisomy 13, respectively. Overall, 602 (3.4%) patients had no-call result after the first draw and 287 (1.61%) after including cases with a second draw. The trisomy rate was higher in the 287 cases with no-call results than patients with a result on a first draw (2.8% vs 0.7%; P=.001). The updated algorithm showed similar sensitivity and specificity to the study algorithm with a lower no-call rate. CONCLUSION: In women at a low risk for aneuploidy, single-nucleotide-polymorphism-based cell-free DNA has high sensitivity and specificity, positive predictive value of 85.7% for trisomy 21 and 74.3% for the 3 common trisomies. Patients who receive a no-call result are at an increased risk of aneuploidy and require additional investigation.

BACKGROUND: Historically, prenatal screening has focused primarily on the detection of fetal aneuploidies. Cell-free DNA now enables noninvasive screening for subchromosomal copy number variants, including 22q11.2 deletion syndrome (or DiGeorge syndrome), which is the most common microdeletion and a leading cause of congenital heart defects and neurodevelopmental delay. Although smaller studies have demonstrated the feasibility of screening for 22q11.2 deletion syndrome, large cohort studies with confirmatory postnatal testing to assess test performance have not been reported. OBJECTIVE: This study aimed to assess the performance of single-nucleotide polymorphismebased, prenatal cell-free DNA screening for detection of 22q11.2 deletion syndrome. STUDY DESIGN: Patients who underwent single-nucleotide polymorphismebased prenatal cell-free DNA screening for 22q11.2 deletion syndrome were prospectively enrolled at 21 centers in 6 countries. Prenatal or newborn DNA samples were requested in all cases for genetic confirmation using chromosomal microarrays. The primary outcome was sensitivity, specificity, positive predictive value, and negative predictive value of cell-free DNA screening for the detection of all deletions, including the classical deletion and nested deletions that are >= 500 kb, in the 22q11.2 low-copy repeat A-D region. Secondary outcomes included the prevalence of 22q11.2 deletion syndrome and performance of an updated cell-free DNA algorithm that was evaluated with blinding to the pregnancy outcome. RESULTS: Of the 20,887 women enrolled, a genetic outcome was available for 18,289 (87.6%). A total of 12 22q11.2 deletion syndrome cases were confirmed in the cohort, including 5 (41.7%) nested deletions, yielding a prevalence of 1 in 1524. In the total cohort, cell-free DNA screening identified 17,976 (98.3%) cases as low risk for 22q11.2 deletion syndrome and 38 (0.2%) cases as high risk; 275 (1.5%) cases were nonreportable. Overall, 9 of 12 cases of 22q11.2 were detected, yielding a sensitivity of 75.0% (95% confidence interval, 42.8-94.5); specificity of 99.84% (95% confidence interval, 99.77-99.89); positive predictive value of 23.7% (95% confidence interval, 11.44-40.24), and negative predictive value of 99.98% (95% confidence interval, 99.95-100). None of the cases with a nonreportable result was diagnosed with 22q11.2 deletion syndrome. The updated algorithm detected 10 of 12 cases (83.3%; 95% confidence interval, 51.6-97.9) with a lower false positive rate (0.05% vs 0.16%; P<.001) and a positive predictive value of 52.6% (10/19; 95% confidence interval, 28.9-75.6). CONCLUSION: Noninvasive cell-free DNA prenatal screening for 22q11.2 deletion syndrome can detect most affected cases, including smaller nested deletions, with a low false positive rate.

We evaluated performance of single-nucleotide polymorphism (SNP)-based cell-free DNA (cfDNA) screening for trisomies 13, 18, and 21 in a large unselected prospective cohort with genetic confirmation. We hypothesized equivalent performance to published studies without genetic confirmation.

Cell free DNA (cfDNA) screening for pathogenic copy number variants (CNV) such as 22q11.2 deletion syndrome (22q11.2DS) is clinically available. Data on test performance are limited. we report on the performance of SNP-based cfDNA in a large prenatal cohort. We hypothesized that SNP-based cfDNA can detect 22q11.2DS deletions that are >500kb. Patients who had SNP-based cfDNA for aneuploidy and 22q11.2DS were recruited at 21 centers in 6 countries. Genetic confirmation was obtained for all pregnancies from prenatal or newborn DNA samples. All microdeletions larger than 500kb associated with 22q11.2DS were included in the test performance analysis, including the 2.5-3Mb LCR22A-D classic deletion as well as smaller nested deletions. An updated cfDNA algorithm that was blinded to pregnancy outcome was also evaluated. Of 20,887 women enrolled, 18,289 (87.6%) had both cfDNA and DNA confirmation results for 22q11.2DS. Mean maternal age and gestational age at enrollment were 33.7 years and 13.3 weeks, respectively. Twelve 22q11.2DS cases were identified by prenatal (n=3) or postnatal (n=9) testing, yielding a cohort prevalence of 1:1524. Deletion sizes are detailed in the table below. The screen positive rate of cfDNA for 22q11.2DS was 0.2% (37/18,289). Sensitivity was 75.0% (95% CI: 50.5, 99.5); specificity was 99.84% (95% CI: 99.79, 99.90); and PPV was 24.3% (95% CI: 10.5, 38.2). Sensitivity, specificity and PPV were all higher using the updated algorithm (83.3%; 99.95%, and 52.6%, respectively) and the screen positive rate was significantly lower (0.1%; p=0.0004). There were no cases of 22q11.2DS in the 1.46% of cases without results (“no call” cases). In a prospective cohort of 18,289 pregnancies with genetic confirmation, SNP-based cfDNA screening for 22q11.2DS had high sensitivity and specificity and detected both classic and nested deletions with a PPV greater than 50% using an updated algorithm.

To evaluate performance of single nucleotide polymorphism (SNP)-based cell-free DNA (cfDNA) screening for detection of trisomies 13, 18, and 21 in a large unselected cohort with genetic confirmation. We hypothesized that performance in all risk groups is equivalent to published studies without genetic confirmation. Unselected pregnant women who had SNP-based cfDNA for T13, T18 and T21 were recruited at 21 centers in 6 countries. Genetic confirmation was obtained for all pregnancies from prenatal or newborn DNA samples. Sensitivity, specificity, PPV and test failure (no call) rates were calculated and compared between women at low and high prior risk for aneuploidy. High risk was defined as having positive serum screening, nuchal translucency >3mm, major fetal anomaly on ultrasound or >35 years old with no prior screening. Performance of an updated cfDNA algorithm, blinded to pregnancy outcome, was also assessed. Of 20,887 women enrolled, 18,496 (88.5%) had genetic confirmation and comprised the study cohort. Mean gestational age at enrollment was 13.2 weeks. 133 (0.72%) cases of trisomy were identified: n=100 T21, n=18 T18 and n=15 T13. 18,205 women received a cfDNA result while 291 (1.57%) were no call. Screen positive rate was lower in low vs high risk cases (0.26% vs 2.1%, p50% for all trisomies. An updated algorithm decreased the no-call rate while maintaining performance.

Failed or no call cell free DNA (cfDNA) testing confers an increased risk of aneuploidy, but few series include complete obstetric, infant, and genetic outcomes. We hypothesized that failed tests would be associated with aneuploidy and adverse perinatal outcomes. Secondary analysis of a multicenter prospective study of SNP-based cfDNA; confirmatory genetic testing was performed in all cases during pregnancy or after birth. Demographics, pregnancy outcomes, and confirmatory genetic results were compared between no call and resulted cases. Univariate analysis compared differences between groups; odds ratios (OR) were calculated after adjusting for BMI, gestational age at draw, and black race. Results applying an updated algorithm after study completion were also compared. 18,496 women had both cfDNA screening and genetic confirmation. A first draw result was reported in 17,885 while 611 (3.3%) were no calls; 320/435 (73.6%) redraws gave a result, leaving 291 as no calls. No calls were associated with higher BMI, later gestational age, lower fetal fraction, and black race. T13, 18, or 21 was confirmed in 1.6% of no calls vs 0.7% with a result (p=.013). After adjustment for confounders, the aOR for aneuploidy was 2.2 (95% CI 1.1,4.5) after a first no call; this increased to 3.8 (95% CI 1.7, 8.4) after the second. Livebirths occurred in 94.9% with a no call vs 98.8% with a result (p< .001; aOR for livebirth: 0.17 [95% CI 0.10, 0.28]). PTB < 28, 34, and 37wks and preeclampsia were all higher after a no call. All risks were higher after a second no call result (Table). With the updated algorithm, the no call rate decreased to 0.6% and the adverse associations were further increased. The association with perinatal outcomes persisted in euploid pregnancies. Patients with no call cfDNA results are at increased risk for aneuploidy; this risk is further increased with a second no call. The risk of other adverse perinatal outcomes is also increased, including in euploid pregnancies.

Down syndrome (DS) is the most common liveborn autosomal chromosomal anomaly and is a major cause of developmental disability. Atypical brain development and the resulting intellectual disability originate during the fetal period. Perinatal interventions to correct such aberrant development are on the horizon in preclinical studies. However, we lack tools to sensitively measure aberrant structural brain development in living human fetuses with DS. In this study, we aimed to develop safe and precise neuroimaging measures to monitor fetal brain development in DS. We measured growth patterns of regional brain structures in 10 fetal brains with DS (29.1 ± 4.2, weeks of gestation, mean ± SD, range 21.7~35.1) and 12 control fetuses (25.2 ± 5.0, range 18.6~33.3) using regional volumetric analysis of fetal brain MRI. All cases with DS had confirmed karyotypes. We performed non-linear regression models to compare fitted regional growth curves between DS and controls. We found decreased growth trajectories of the cortical plate (P = 0.033), the subcortical parenchyma (P = 0.010), and the cerebellar hemispheres (P < 0.0001) in DS compared to controls. This study provides proof of principle that regional volumetric analysis of fetal brain MRI facilitates successful evaluation of brain development in living fetuses with DS.

To compare the intrauterine inflammation and microbiota in amniotic fluid (AF) in asymptomatic singleton gestations with either short cervical length (CL) or dilated cervix during the second trimester compared with normal CL. Amniotic fluid (AF) was collected from a prospective cohort of asymptomatic singleton pregnancies 16-24 weeks in three clinical categories: normal CL undergoing genetic amniocentesis (n=5), CL< 25 mm (n=3) or dilated cervix 1-4cm (n=11) prior to cerclage placement. Cases of genetic/fetal anomalies or chorioamnionitis were excluded. Bacterial genomic DNA was extracted and V3-V5 regions of the 16S rRNA gene were amplified to identify the microbiome content and compared to phlyogenetic reference bacterial genomes. Cytokine levels were assessed by multiplex analysis using a Bio-Plex Pro Human 17-plex assay platform with sensitivity <3pg/ml. Statistical analysis was performed using non-parametric tests. Clinical data and median AF cytokine levels are presented (Table). The most commonly observed bacterium genera were actinobacteria (28.6%) and proteobacteria (20.2%) (Figure). There were no significant differences in the microbial communities in the three group of women. Dilated cervix AF-samples were significantly more alike than those from either short or normal CL (p<0.01). IL-6, IL-1β, IL-8, IL-10, MCP-1 and MIP-1b were significantly elevated in AF of cases with dilated cervix. AF cytokines from CL< 25 mm were similar to controls (Table). These AF inflammatory changes were associated with a significantly shorter latency period (amniocentesis to delivery) and earlier GA at delivery in cases with dilated cervix. Microbiome community in the AF was similar in the three groups. Inflammation activation was more associated with cervical dilation in the second trimester compared to normal CL or short CL. Shorter latency period and earlier GA at delivery may be secondary to inflammatory changes rather than microbiome community in AF.

BACKGROUND:In high-risk pregnant women, noninvasive prenatal testing with the use of massively parallel sequencing of maternal plasma cell-free DNA (cfDNA testing) accurately detects fetal autosomal aneuploidy. Its performance in low-risk women is unclear.METHODS:At 21 centers in the United States, we collected blood samples from women with singleton pregnancies who were undergoing standard aneuploidy screening (serum biochemical assays with or without nuchal translucency measurement). We performed massively parallel sequencing in a blinded fashion to determine the chromosome dosage for each sample. The primary end point was a comparison of the false positive rates of detection of fetal trisomies 21 and 18 with the use of standard screening and cfDNA testing. Birth outcomes or karyotypes were the reference standard.RESULTS:The primary series included 1914 women (mean age, 29.6 years) with an eligible sample, a singleton fetus without aneuploidy, results from cfDNA testing, and a risk classification based on standard screening. For trisomies 21 and 18, the false positive rates with cfDNA testing were significantly lower than those with standard screening (0.3% vs. 3.6% for trisomy 21, P<0.001; and 0.2% vs. 0.6% for trisomy 18, P=0.03). The use of cfDNA testing detected all cases of aneuploidy (5 for trisomy 21, 2 for trisomy 18, and 1 for trisomy 13; negative predictive value, 100% [95% confidence interval, 99.8 to 100]). The positive predictive values for cfDNA testing versus standard screening were 45.5% versus 4.2% for trisomy 21 and 40.0% versus 8.3% for trisomy 18.CONCLUSIONS:In a general obstetrical population, prenatal testing with the use of cfDNA had significantly lower false positive rates and higher positive predictive values for detection of trisomies 21 and 18 than standard screening. (Funded by Illumina; ClinicalTrials.gov number, NCT01663350.).

Noninvasive prenatal screening (NIPS) has emerged as a highly accurate method of screening for fetal Down syndrome, with a detection rate and specificity approaching 100%. Challenging the widespread use of this technology are cost and the paradigm shift in counseling that accompanies any emerging technology. The expense of the test is expected to decrease with increased utilization, and well beyond the current NIPS technology, its components (fetal genome measurements, sequencing technology, and bioinformatics) will be utilized alone or in combinations to interrogate the fetal genome. The end goal is simple: to offer patients information early in pregnancy about fetal genomes without incurring procedural risks. This will allow patients an opportunity to make informed reproductive and pregnancy management decisions based on precise fetal genomic information.

Objective: To characterize skin wrinkles and rigidity in recently menopausal women.Design: Baseline assessment of participants before randomization to study drug.Setting: Multicenter trial, university medical centers.Patient(s): Recently menopausal participants enrolled in the Kronos Early Estrogen Prevention Study (KEEPS).Intervention(s): Skin wrinkles were assessed at 11 locations on the face and neck using the Lemperle wrinkle scale. Skin rigidity was assessed at the forehead and cheek using a durometer.Main Outcome Measure(s): Skin wrinkles and rigidity were compared among race/ethnic groups. Skin wrinkles and rigidity were correlated with age, time since menopause, weight, and body mass index (BMI).Result(s): In early menopausal women, wrinkles, but not skin rigidity, vary significantly among races, where black women have the lowest wrinkle scores. In white women, chronological age was significantly correlated with worsening skin wrinkles, but not with rigidity. Skin rigidity correlated with increasing length of time since menopause, however, only in the white subgroup. In the combined study group, increasing weight was associated with less skin wrinkling.Conclusion(s): Skin characteristics of recently menopausal women are not well studied. Ethnic differences in skin characteristics are widely accepted, but poorly described. In recently menopausal women not using hormone therapy (HT), significant racial differences in skin wrinkling and rigidity exist. Continued study of the KEEPS population will provide evidence of the effects of HTon the skin aging process in early menopausal women. (Fertil Steril (R) 2011;95:658-62. (C) 2011 by American Society for Reproductive Medicine.)