Combined first-trimester screening and invasive diagnostics for atypical chromosomal aberrations: Danish nationwide data on prenatal profiles and detection compared with NIPT.

OBJECTIVE: To examine the prenatal profiles of pregnancies affected by an atypical chromosomal aberration, focusing on pathogenic copy number variants (pCNVs). Further, we wanted to quantify the performance of combined first-trimester screening (cFTS) and a second-trimester anomaly scan in detecting these conditions. Finally, we aimed to estimate the consequences of a policy of using non-invasive prenatal testing (NIPT) rather than invasive testing with chromosomal microarray (CMA) to manage pregnancies identified as high risk from cFTS. METHODS: A retrospective review of the Danish fetal medicine database identified all pregnant women who had cFTS and a trisomy 21 risk-assessment between January 1, 2008, and December 31, 2018. Chromosomal aberrations diagnosed prenatally, postnatally, or from fetal tissue following pregnancy loss or termination of pregnancy (TOP) were identified. Chromosomal aberrations were grouped into one of six categories: 1) Triploidy; 2) Common trisomies (trisomies 21, 18, and 13); 3) Monosomy X; 4) Other sex chromosome aberrations (SCAs); 5) pCNVs; and 6) Rare autosomal trisomies (RATs) and mosaicisms. The prevalence of each aberration-category was stratified by the individual cFTS markers and risk estimate, and the size of each pCNV diagnosed from CMA was calculated. RESULTS: We included data on 565,708 pregnancies of which 3,982 were diagnosed with a fetal chromosomal aberration (0.70%). cFTS performed well in identifying triploidies (86%), monosomy X (92%), atypical SCAs (58%), and RATs and mosaicisms (70%). pCNVs comprised 28% (n = 1,091) of the chromosomal aberrations diagnosed overall, and the prevalence increased during the study period with more prenatal chromosomal microarray analysis being performed. In pregnancies with maternal age <30 years, NT <95th percentile, PAPP-A MoM ≥ 1, or trisomy 21 risk ≥1 in 1000, the prevalence of pCNVs significantly exceeded the prevalence of trisomies 21, 18, and 13. Pregnancies affected by a pCNV had significantly increased nuchal translucency thickness (NT) and decreased maternal biomarkers pregnancy associated plasma protein-A (PAPP-A) and ß-human chorionic gonadotropin (ß-hCG) compared with unaffected pregnancies. However, only 23% of these pregnancies screened positive from cFTS and 51% were not detected until after birth. Amongst high-risk pregnancies diagnosed with a chromosomal aberration, pCNVs comprised 14% and when other atypical aberrations were considered, conventional NIPT (screening for trisomies 21, 18, and 13, and monosomy X) would miss 28% of all pathogenic aberrations diagnosed following a high-risk cFTS result. Thus, 1 in 26 pregnancies at high-risk following cFTS would be affected by a chromosomal aberration despite a normal conventional NIPT result. In a contingent screening model with NIPT provided for the "intermediate" risk group (T21 risk of 1 in 100-300), 50% of the aberrations would be missed. In our cohort, 80% of the pCNVs diagnosed were <5Mb and therefore not detectable using current forms of "genome wide" NIPT. CONCLUSION: As a by-product to screening for trisomies 21, 18, and 13, most triploidies and the majority of atypical SCAs, RATs, and mosaicisms are detected before birth. However, only 23% of pCNVs are high-risk from cFTS and only half are diagnosed before birth. Replacing invasive testing with NIPT for high-risk pregnancies would substantially decrease the first-trimester detection of pathogenic chromosomal anomalies. This article is protected by copyright. All rights reserved.

Decoding 22q11.2: prenatal profiling and first-trimester risk assessment in Danish nationwide cohort.

OBJECTIVES: To examine the distribution of nuchal translucency thickness (NT), free ß-human chorionic gonadotropin (ß-hCG) and pregnancy-associated plasma protein-A (PAPP-A) in pregnancies with a fetal 22q11.2 aberration. Furthermore, the performance of combined first-trimester screening (cFTS) and a new risk algorithm targeting 22q11.2 deletions in detecting affected pregnancies was evaluated. Finally, prenatal malformations and pregnancy outcome were assessed. METHODS: This was a nationwide registry-based cohort study of all pregnancies that underwent prenatal screening with a due date between January 2008 and December 2018 in Denmark. All cases with a fetal 22q11.2 deletion or duplication (hg19 chr22:18.9mio-25.0mio) diagnosed pre- or postnatally or following pregnancy loss or termination of pregnancy were retrieved from the Danish Cytogenetic Central Register and linked with pregnancy data from the Danish Fetal Medicine Database. Fetal and maternal characteristics, including cFTS results and pregnancy outcome, of pregnancies with any 22q11.2 deletion or duplication (LCR22-A to -H) and pregnancies with a classic deletion or duplication (LCR22-A to -D) diagnosed by chromosomal microarray were compared with those of a chromosomally normal reference group. A risk algorithm was developed for assessing patient-specific risks for classic 22q11.2 deletions based on NT, PAPP-A and ß-hCG. Detection rates and false-positive rates at different risk cut-offs were calculated. RESULTS: We included data on 143 pregnancies with a fetal 22q11.2 aberration, of which 97 were deletions (54 classic) and 46 were duplications (32 classic). NT was significantly increased in fetuses with a classic deletion (mean, 1.89 mm), those with any deletion (mean, 1.78 mm) and those with any duplication (mean, 1.86 mm) compared to the reference group (mean, 1.65 mm). ß-hCG multiples of the median (MoM) was decreased in all 22q11.2 subgroups compared with the reference group (mean, 1.02) and reached significance in pregnancies with a classic deletion and those with any deletion (mean, 0.77 and 0.71, respectively). PAPP-A MoM was significantly decreased in pregnancies with a classic duplication and those with any duplication (mean, 0.57 and 0.63, respectively), and was significantly increased in pregnancies with a classic deletion and those with any deletion (mean, 1.34 and 1.16, respectively), compared to reference pregnancies (mean, 1.01). The screen-positive rate by cFTS was significantly increased in pregnancies with a classic deletion (13.7%), any deletion (12.5%), a classic duplication (46.9%) or any duplication (37.8%) compared to the reference group (4.5%). A risk algorithm targeting classic 22q11.2 deletions more than doubled the prenatal detection rate of classic 22q11.2 deletions, but with a substantial increase in the false-positive rate. Structural malformations were detected in 41%, 35%, 17% and 25% of the pregnancies with a classic deletion, any deletion, classic duplication or any duplication, respectively. Pregnancy loss occurred in 40% of pregnancies with a classic deletion and 5% of those with a classic duplication diagnosed prenatally or following pregnancy loss. CONCLUSIONS: The distribution of cFTS markers in pregnancies with a classic 22q11.2 duplication resembles that of the common trisomies, with decreased levels of PAPP-A. However, classic 22q11.2 deletions are associated with increased levels of PAPP-A, which likely limits early prenatal detection using the current cFTS risk algorithm. The scope for improving early detection of classic 22q11.2 deletions using targeted risk algorithms based on NT, PAPP-A and ß-hCG is limited. This demonstrates the capability, but also the limitations, of cFTS markers in detecting atypical chromosomal anomalies, which is important knowledge when designing new prenatal screening programs. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Vaginal progesterone for prevention of preterm birth in asymptomatic high-risk women with a normal cervical length: a systematic review and meta-analysis.

Objective: To determine whether vaginal progesterone reduces spontaneous preterm birth (sPTB) before 37 weeks in asymptomatic high-risk women with a singleton pregnancy and normal mid-gestation cervical length.Study design: Databases were searched (from inception to December 2020) with the search terms "progesterone" and "premature birth" or "preterm birth". Studies were screened and included if they assessed vaginal progesterone compared to placebo in women with normal cervical length. Data were pooled and synthesized in a meta-analysis using a random effects model.Data sources: MEDLINE and Embase databases.Study synthesis: Following PRISMA screening guidelines, data from 1127 women across three studies were available for synthesis. All studies had low risk of bias and were of high quality. The primary outcome was sPTB <37 weeks, with secondary outcomes of sPTB <34 weeks. Vaginal progesterone did not significantly reduce sPTB before 37 weeks, or before 34 weeks with a relative risk (RR) of 0.76 (95% CI 0.37-1.55, p = .45) and 0.51 (95% CI 0.12-2.13, p = .35), respectively.Conclusions: Vaginal progesterone does not decrease the risk of sPTB in high-risk singleton pregnancies with a normal mid-gestation cervical length.

Impact of analysis technique on our understanding of the natural history of labour: a simulation study.

OBJECTIVE: To evaluate the discrepancy between historical and more recent descriptions of the first stage of labour by testing whether the statistical techniques used recently (repeated-measures polynomial and interval-censored regression) were appropriate for detection of periods of rapid acceleration of cervical dilatation as might occur at the time of transition from a latent to an active phase of labour. DESIGN AND SETTING: A simulation study using regression techniques. SAMPLE: We created a simulated data set for 500 000 labours with clearly defined latent and active phases using the parameters described by Friedman. Additionally, we created a data set comprising 500 000 labours with a progressively increasing rate of cervical dilatation. METHODS: Repeated-measures polynomial regression was used to create summary labour curves based on simulated cervical examinations. Interval-censored regression was used to create centimetre-by-centimetre estimates of rates of cervical dilatation and their 95th centiles. MAIN OUTCOME MEASURES: Labour summary curves and rates of cervical dilatation. RESULTS: Repeated-measures polynomial regression did not detect the rapid acceleration in cervical dilatation (i.e. acceleration phase) and overestimated lengths of labour, especially at smaller cervical dilatations. There was a two-fold overestimation in the mean rate of cervical dilatation from 4 to 6 cm. Interval-censored regression overestimated median transit times, at 4- to 5-cm cervical dilatation or when cervical examinations occurred less frequently than 0.5- to 1.5-hourly. CONCLUSION: Repeated-measures polynomial regression and interval-censored regression should not be routinely used to define labour progress because they do not accurately reflect the underlying data. TWEETABLE ABSTRACT: Repeated-measures polynomial and interval-censored regression techniques are not appropriate to model first stage of labour.

Cost-effectiveness analysis of a model of first-trimester prediction and prevention of preterm pre-eclampsia compared with usual care.

OBJECTIVES: Pre-eclampsia (PE) causes substantial maternal and neonatal mortality and morbidity. In addition to the personal impact on women, children and their families, PE has a significant economic impact on our society. Recent research suggests that a first-trimester multivariate model is highly predictive of preterm (< 37 weeks' gestation) PE and can be combined successfully with targeted prophylaxis (low-dose aspirin), resulting in an 80% reduction in prevalence of disease. The aim of this study was to examine the potential health outcomes and cost implications following introduction of first-trimester prediction and prevention of preterm PE within a public healthcare setting, compared with usual care, and to conduct a cost-effectiveness analysis to inform health-service decisions regarding implementation of such a program. METHODS: A decision-analytic model was used to compare usual care with the proposed first-trimester screening intervention within the obstetric population (n = 6822) attending two public hospitals within a metropolitan district health service in New South Wales, Australia, between January 2015 and December 2016. The model, applied from early pregnancy, included exposure to a variety of healthcare professionals and addressed type of risk assessment (usual care or first-trimester screening) and use of (compliance with) low-dose aspirin prescribed prophylactically for prevention of PE. All pathways culminated in six possible health outcomes, ranging from no PE to maternal death. Results were presented as the number of cases of PE gained/avoided and the incremental increase/decrease in economic costs arising from the intervention compared with usual care. Significant assumptions were tested in sensitivity/uncertainty analyses. RESULTS: The intervention produced, across all gestational ages, 31 fewer cases of PE and reduced aggregate economic health-service costs by 1 431 186 Australian dollars over the 2-year period. None of the tested iterations of uncertainty analyses reported additional cases of PE or higher economic costs. The new intervention based on first-trimester screening dominated usual care. CONCLUSION: This cost-effectiveness analysis demonstrated a reduction in prevalence of preterm PE and substantial cost savings associated with a population-based program of first-trimester prediction and prevention of PE, and supports implementation of such a policy. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

Performance of six birth-weight and estimated-fetal-weight standards for predicting adverse perinatal outcome: a 10-year nationwide population-based study.

OBJECTIVE: To evaluate three birth-weight (BW) standards (Australian population-based, Fenton and INTERGROWTH-21st ) and three estimated-fetal-weight (EFW) standards (Hadlock, INTERGROWTH-21st and WHO) for classifying small-for-gestational age (SGA) and large-for-gestational age (LGA) and predicting adverse perinatal outcomes in preterm and term babies. METHODS: This was a nationwide population-based study conducted on a total of 2.4 million singleton births that occurred from 24 + 0 to 40 + 6 weeks' gestation between 2004 and 2013 in Australia. The performance of the growth charts was evaluated according to SGA and LGA classification, and relative risk (RR) and diagnostic accuracy based on the areas under the receiver-operating-characteristics curves (AUCs) for stillbirth, neonatal death, perinatal death, composite morbidity and a composite of perinatal death and morbidity outcomes. The analysis was stratified according to gestational age at delivery (< 37 + 0 vs ≥ 37 + 0 weeks). RESULTS: Following exclusions, 2 392 782 singleton births were analyzed. There were significant differences in the SGA and LGA classification and risk of adverse outcomes between the six BW and EFW standards evaluated. For the term group, compared with the other standards, the INTERGROWTH-21st BW and EFW standards classified half the number of SGA (< 10th centile) babies (3-4% vs 7-11%) and twice the number of LGA (> 90th centile) babies (24-25% vs 8-15%), resulting in a smaller cohort of term SGA at higher risk of adverse outcome and a larger LGA cohort at lower risk of adverse outcome. For term SGA (< 3rd centile) babies, the RR of perinatal death using the two INTERGROWTH-21st standards was up to 1.5-fold higher than those of the other standards (including the WHO-EFW and Hadlock-EFW), while the INTERGROWTH-21st -EFW standard indicated a 12-26% reduced risk of perinatal death for LGA cases across centile thresholds. Conversely, for the preterm group, the WHO-EFW and Hadlock-EFW standards identified a higher SGA classification rate than did the other standards (18-19% vs 10-11%) and a 20-65% increased risk of perinatal death in term LGA babies. All BW and EFW charts had similarly poor performance in predicting adverse outcomes, including the composite outcome (AUC range, 0.49-0.62) for both preterm (AUC range, 0.58-0.62) and term (AUC range, 0.49-0.50) cases and across centiles. Furthermore, specific centile thresholds for identifying adverse outcomes varied markedly by chart between BW and EFW standards. CONCLUSIONS: This study addresses the recurrent problem of identifying fetuses at risk of morbidity and perinatal mortality associated with growth disorders and provides new insights into the applicability of international growth standards. Our findings of marked variation in classification and the similarly poor performance of prescriptive international standards and the other commonly used standards raise questions about whether the prescriptive international standards that were constructed for universal adoption are indeed applicable to a multiethnic population such as that of Australia. Thus, caution is needed when adopting universal standards for clinical and epidemiological use. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

Ultrasound features prior to 11 weeks' gestation and first-trimester maternal factors in prediction of hypertensive disorders of pregnancy.

OBJECTIVES: Maternal hypertensive disorders (MHD), including pregnancy-induced hypertension and pre-eclampsia, are estimated to occur in 7-10% of pregnancies worldwide and have significant short- and long-term implications for both mother and fetus. This study aimed to determine the association of conventional and novel early first-trimester ultrasound measures with MHD and whether these ultrasound measures, combined with maternal characteristics and biochemistry, improve the prediction of MHD. METHODS: This was a prospective cohort study of consecutive women with a singleton pregnancy, attending for an early (5 + 1 to 11 + 0 weeks' gestation) ultrasound examination at a private obstetric ultrasound practice between February 2016 and August 2018. Recorded ultrasound measurements included mean sac diameter, yolk sac diameter, crown-rump length, fetal heart rate (FHR), trophoblast thickness, trophoblast volume (TV) and mean uterine artery pulsatility index. Maternal biochemistry was assessed at 10-14 weeks and included beta-human chorionic gonadotropin, pregnancy-associated plasma protein-A (PAPP-A), placental growth factor (PlGF) and maternal serum alpha-fetoprotein. Regression models were fitted for each ultrasound parameter and multiples of the median (MoM) were calculated. All measures were compared between women who had a normotensive outcome and those who subsequently developed MHD. Logistic regression analysis was used to create a prediction model for MHD based on maternal characteristics, ultrasound measurements at 5 + 1 to 11 + 0 weeks' gestation and maternal biochemistry at 10-14 weeks. RESULTS: In total, 1141 women were included in the analysis, of whom 1086 (95.2%) were normotensive at delivery and 55 (4.8%) developed MHD. Women who developed MHD weighed significantly more than did normotensive women (P < 0.0001). Mean MoM values for TV (P = 0.006), PAPP-A (P = 0.031) and PlGF (P = 0.044) were decreased significantly in pregnancies that subsequently developed MHD. The proposed logistic regression model includes maternal weight and height and MoM values for TV, FHR and PlGF, resulting in an area under the receiver-operating-characteristics curve of 0.80 (95% CI, 0.75-0.86). CONCLUSION: The combination of maternal weight and height, TV and FHR, measured prior to 11 weeks' gestation, and first-trimester PlGF appears to have good predictive value for development of MHD later in pregnancy. Copyright © 2020 ISUOG. Published by John Wiley & Sons Ltd.

STRIDER NZAus: a multicentre randomised controlled trial of sildenafil therapy in early-onset fetal growth restriction.

OBJECTIVE: To assess the effect of maternal sildenafil therapy on fetal growth in pregnancies with early-onset fetal growth restriction. DESIGN: A randomised placebo-controlled trial. SETTING: Thirteen maternal-fetal medicine units across New Zealand and Australia. POPULATION: Women with singleton pregnancies affected by fetal growth restriction at 22+0 to 29+6 weeks. METHODS: Women were randomised to oral administration of 25 mg sildenafil citrate or visually matching placebo three times daily until 32+0 weeks, birth or fetal death (whichever occurred first). MAIN OUTCOME MEASURES: The primary outcome was the proportion of pregnancies with an increase in fetal growth velocity. Secondary outcomes included live birth, survival to hospital discharge free of major neonatal morbidity and pre-eclampsia. RESULTS: Sildenafil did not affect the proportion of pregnancies with an increase in fetal growth velocity; 32/61 (52.5%) sildenafil-treated, 39/57 (68.4%) placebo-treated [adjusted odds ratio (OR) 0.49, 95% CI 0.23-1.05] and had no effect on abdominal circumference Z-scores (P = 0.61). Sildenafil use was associated with a lower mean uterine artery pulsatility index after 48 hours of treatment (1.56 versus 1.81; P = 0.02). The live birth rate was 56/63 (88.9%) for sildenafil-treated and 47/59 (79.7%) for placebo-treated (adjusted OR 2.50, 95% CI 0.80-7.79); survival to hospital discharge free of major neonatal morbidity was 42/63 (66.7%) for sildenafil-treated and 33/59 (55.9%) for placebo-treated (adjusted OR 1.93, 95% CI 0.84-4.45); and new-onset pre-eclampsia was 9/51 (17.7%) for sildenafil-treated and 14/55 (25.5%) for placebo-treated (OR 0.67, 95% CI 0.26-1.75). CONCLUSIONS: Maternal sildenafil use had no effect on fetal growth velocity. Prospectively planned meta-analyses will determine whether sildenafil exerts other effects on maternal and fetal/neonatal wellbeing. TWEETABLE ABSTRACT: Maternal sildenafil use has no beneficial effect on growth in early-onset FGR, but also no evidence of harm.

Cost-effectiveness of first-trimester screening with early preventative use of aspirin in women at high risk of early-onset pre-eclampsia.

OBJECTIVE: Pre-eclampsia (PE) remains a leading cause of maternal and fetal morbidity and mortality. A first-trimester screening algorithm predicting the risk of early-onset PE has been developed and validated. Early prediction coupled with initiation of aspirin at 11-13 weeks in women identified as high risk is effective at reducing the prevalence of early-onset PE. The aim of this study was to evaluate the cost-effectiveness of this first-trimester screening program coupled with early use of low-dose aspirin in women at high risk of developing early-onset PE, in comparison to current practice in Canada. METHODS: A decision analysis was performed based on a theoretical population of 387 516 live births in Canada in 1 year. The clinical and financial impact of early preventative screening using the Fetal Medicine Foundation algorithm for prediction of early-onset PE coupled with early (< 16 weeks) use of low-dose aspirin in those at high risk was simulated and compared with current practice using decision-tree analysis. The probabilities at each decision point and associated costs of utilized resources were calculated based on published literature and public databases. RESULTS: Of the theoretical 387 516 births per year, the estimated prevalence of early PE based on first-trimester screening and aspirin use was 705 vs 1801 cases based on the current practice. This was associated with an estimated total cost of C$9.52 million with the first-trimester screening program compared with C$23.91 million with current practice for the diagnosis and management of women with early-onset PE. This equals an annual cost saving to the Canadian healthcare system of approximately C$14.39 million. CONCLUSIONS: The implementation of a first-trimester screening program for PE and early intervention with aspirin in women identified as high risk for early PE has the potential to prevent a significant number of early-onset PE cases with a substantial associated cost saving to the healthcare system in Canada. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

Quality assessment of uterine artery Doppler measurement in first-trimester combined screening for pre-eclampsia.

OBJECTIVE: To assess the quality of mean uterine artery (UtA) pulsatility index (PI) measurement in a first-trimester pre-eclampsia screening program. METHODS: Consecutive women with a singleton pregnancy attending first-trimester screening for fetal chromosomal abnormalities also had combined screening for pre-eclampsia based on the Fetal Medicine Foundation (FMF) algorithm, at a large practice in Sydney, Australia, from May 2014 to February 2017. Distributions of mean UtA-PI multiples of the median (MoM) on a logarithmic scale were plotted in relation to the normal median with 95% CI for each operator and for each month. Central tendency and dispersion and cumulative sum charts were produced. Mean UtA-PI MoM values between 0.95 and 1.05 were considered ideal and those between 0.90 and 1.10 were considered acceptable. The screen-positive rates for preterm pre-eclampsia in different groups of sonographers according to their mean log10 UtA-PI MoM were calculated and compared using the chi-square test. RESULTS: A total of 21 010 women attended for first-trimester ultrasound and had screening for pre-eclampsia. The overall median UtA-PI MoM was 1.042 (interquartile range (IQR), 0.85-1.26). Of 46 sonographers, 42 (91.3%) performed more than 50 examinations and, of those, 41 (97.6%) measured UtA-PI within the acceptable range. Sonographers measuring UtA-PI MoM on average below 0.95 and those measuring it above 1.05 had, respectively, lower and higher screen-positive rates when compared with those with measurements within the 0.95-1.05 UtA-PI MoM interval (7.2% and 13.2% vs 11.2%, respectively, P < 0.001). CONCLUSION: UtA Doppler is measured well among trained operators when following an established protocol. While slight variations are expected, systematic error in this measurement impacts on the screen-positive rate. Therefore, a quality control process should be in place and retraining of staff may be required. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

Maternal and perinatal outcomes after elective induction of labor at 39 weeks in uncomplicated singleton pregnancy: a meta-analysis.

OBJECTIVE: The rate of maternal and perinatal complications increases after 39 weeks' gestation in both unselected and complicated pregnancies. The aim of this study was to synthesize quantitatively the available evidence on the effect of elective induction of labor at 39 weeks on the risk of Cesarean section, and on maternal and perinatal outcomes. METHODS: PubMed, US Registry of Clinical Trials, SCOPUS and CENTRAL databases were searched from inception to August 2018. Additionally, the references of retrieved articles were searched. Eligible studies were randomized controlled trials of singleton uncomplicated pregnancies in which participants were randomized between 39 + 0 and 39 + 6 gestational weeks to either induction of labor or expectant management. The risk of bias of individual studies was assessed using the Cochrane Risk of Bias Tool. The overall quality of evidence was assessed according to the GRADE guideline. Primary outcomes included Cesarean section, maternal death and admission to the neonatal intensive care unit (NICU). Secondary outcomes included operative delivery, Grade-3/4 perineal laceration, postpartum hemorrhage, maternal infection, hypertensive disease of pregnancy, maternal thrombotic events, length of maternal hospital stay, neonatal death, need for neonatal respiratory support, cerebral palsy, length of stay in NICU and length of neonatal hospital stay. Pooled risk ratios (RRs) were calculated using random-effects models. RESULTS: The meta-analysis included five studies (7261 cases). Induction of labor was associated with a decreased risk for Cesarean section (moderate quality of evidence; RR 0.86 (95% CI, 0.78-0.94); I2  = 0.1%), maternal hypertension (moderate quality of evidence; RR 0.65 (95% CI, 0.57-0.75); I2  = 0%) and neonatal respiratory support (moderate quality of evidence; RR 0.73 (95% CI, 0.58-0.95); I2  = 0%). Neonates born after induction weighed, on average, 81 g (95% CI, 63-100 g) less than those born after expectant management. No significant effects were found for the other outcomes with the available data. The main limitation of our analysis was that the majority of data were derived from a single large study. A second limitation arose from the open-label design of the studies, which may theoretically have affected the readiness of the attending clinician to resort to Cesarean section. CONCLUSIONS: Elective induction of labor in uncomplicated singleton pregnancy at 39 weeks' gestation is not associated with maternal or perinatal complications and may reduce the need for Cesarean section, risk of hypertensive disease of pregnancy and need for neonatal respiratory support. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

Chromosomal microarray as primary diagnostic genomic tool for pregnancies at increased risk within a population-based combined first-trimester screening program.

OBJECTIVE: To evaluate the performance of high-resolution chromosomal microarray (CMA) as the standard diagnostic approach for genomic imbalances in pregnancies with increased risk based on combined first-trimester screening (cFTS). METHODS: This was a retrospective study of genomic findings in a cohort of 575 consecutive pregnancies undergoing invasive testing because of a cFTS risk ≥ 1:300 on a publicly funded population-based screening program in the Central and Northern Regions of Denmark, between September 2015 and September 2016. Women with fetal nuchal translucency thickness ≥ 3.5 mm or opting for non-invasive prenatal testing (NIPT) were excluded. Comparative genomic hybridization was performed using a 180-K oligonucleotide array on DNA extracted directly from chorionic villus/amniocentesis samples. Genomic outcomes were reported in relation to cFTS findings. RESULTS: Of the 575 pregnancies that underwent invasive testing, CMA detected 22 (3.8% (95% CI, 2.5-5.7%)) cases of trisomies 21, 18 and 13, 14 (2.4% (95% CI, 1.4-4.0%)) cases of other types of aneuploidy and 15 (2.6% (95% CI, 1.5-4.3%)) cases with a pathogenic or probably pathogenic copy number variant (CNV). Of the 15 CNVs, three were > 10 Mb and would probably have been detected by chromosomal analysis, but the other 12 would most probably not have been detected using conventional cytogenetic techniques; therefore, the overall detection rate of CMA (8.9% (95% CI, 6.8-11.5%)) was significantly higher than that estimated for conventional cytogenetic analysis (6.8% (95% CI, 5.0-9.1%)) (P = 0.0049). Reducing the cFTS risk threshold for invasive diagnostic testing to 1 in 100 or 1 in 50 would have led, respectively, to 60% or 100% of the pathogenic CNVs being missed. CONCLUSIONS: CMA is a valuable diagnostic technique that can identify an increased number of genomic aberrations in pregnancies at increased risk on cFTS. Limiting diagnostic testing to pregnancies with a risk above 1 in 100 or 1 in 50, as proposed in contingent NIPT/invasive testing models, would lead to a significant proportion of pathogenic CNVs being missed at first-trimester screening. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Identification and management of fetal isolated right-sided aortic arch in an unselected population.

OBJECTIVE: Inclusion of the three vessels and trachea view in the routine assessment of the fetal heart at the 18-20-week morphology scan improves recognition of a right-sided aortic arch (RAA). We report our experience of RAA diagnosed in an unselected population of pregnant women attending for a routine morphology scan. METHODS: The obstetric imaging databases of two ultrasound centers were reviewed retrospectively to identify all routine fetal morphology scans performed at 18-22 weeks' gestation between January 2011 and December 2014. A review of postnatal charts was conducted to ascertain findings at birth, neonatal complications and the anatomical findings at any neonatal echocardiographic or surgical procedure. Parents of older infants were contacted by phone to assess their wellbeing and identify any respiratory or feeding difficulties. RESULTS: In the 48-month study period, 43 083 routine anomaly scans were performed. Twenty-three cases of isolated RAA were identified, a prevalence of 0.05%. Nineteen (83%) cases of isolated RAA had a left-sided arterial duct and four (17%) had a right-sided duct. Postnatal follow-up data were obtained in all cases. The prevalence of a symptomatic vascular ring due to a double aortic arch was 13% (3/23). One (4%) case was diagnosed with DiGeorge syndrome. CONCLUSIONS: RAA can be identified easily on a routine fetal anomaly scan, however the prevalence of RAA is low in an unselected population. Antenatally diagnosed cases should be referred for detailed fetal echocardiography and the patient should be made aware of the association with DiGeorge syndrome and the symptoms associated with a vascular ring. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

IFPA meeting 2015 workshop report II: mechanistic role of the placenta in fetal programming; biomarkers of placental function and complications of pregnancy.

Workshops are an integral component of the annual International Federation of Placenta Association (IFPA) meeting, allowing for networking and focused discussion related to specialized topics on the placenta. At the 2015 IFPA meeting (Brisbane, Australia) twelve themed workshops were held, three of which are summarized in this report. These workshops focused on various aspects of placental function, particularly in cases of placenta-mediated disease. Collectively, these inter-connected workshops highlighted the role of the placenta in fetal programming, the use of various biomarkers to monitor placental function across pregnancy, and the clinical impact of novel diagnostic and surveillance modalities in instances of late onset fetal growth restriction (FGR).

Effect of corticosteroids on cardiac function in growth-restricted fetuses.

OBJECTIVE: To determine the acute effects of corticosteroids on the cardiovascular system in growth-restricted fetuses. METHODS: This was a prospective cohort study conducted at a tertiary hospital between January 2011 and October 2013. Fetal cardiovascular function in fetuses with intrauterine growth restriction (IUGR) was assessed immediately before and 24 h after the first dose of betamethasone, administered in routine management of IUGR. Fetal arterial and venous Dopplers were assessed. Fetal cardiac function was evaluated by tissue Doppler echocardiography, with the assessment of both left and right ventricular function by calculating myocardial performance index (MPI') and E':A' ratios. Values were compared before and after exposure. RESULTS: Seventeen patients were included at a mean gestational age of 34 + 1 (range, 29 + 1 to 37 + 4) weeks. Fifteen fetuses were below the 5(th) percentile and two were below the 10(th) percentile for estimated fetal weight and abdominal circumference and all had no interval growth during a 2-week period. There was a decrease in right MPI' (from 0.56 to 0.47; P = 0.007) after corticosteroid exposure but no change in left MPI' (from 0.49 to 0.48). Right MPI' was higher than left MPI' before exposure (0.56 vs 0.49, respectively; P = 0.001), but not after exposure (P = 0.55). There was no change in left or right ventricular E':A' ratios and no difference was detected in umbilical artery, middle cerebral artery or ductus venosus pulsatility index following administration of corticosteroids. CONCLUSIONS: Corticosteroids altered right-sided, but not left-sided, tissue Doppler MPI' in IUGR fetuses, with no detectable change in arterial or venous Doppler pulsatility indices. Before exposure, the mean right MPI' was higher than the left. However, after exposure, there was no difference, suggesting that corticosteroids may reverse the negative effect of IUGR on fetal heart function. Large prospective studies with a larger sample size are needed to confirm this finding. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.