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Introduction: We aim to evaluate the supplementary predictive value of soft tissue markers, including fetal limb volumes, for fetal birth weight and fat tissue weight., Methods: This is a prospective study of 60 patients undergoing term induction of labor. Ultrasound was performed 48 h before birth, and 2D sonographic measurements, subcutaneous tissue thickness, and 3D fetal limb volumes were taken. Birth weight and neonatal fat weight were assessed by plethysmography. Clinical data were collected. The relation between ultrasound and neonatal outcomes was assessed by univariate and multivariate predictive models. The estimated and actual birth weights were compared applying different published formulas, and systematic and random error were collected and compared., Results: 3D fetal limb volumes showed a strong relation to birth weight, absolute weight, and relative fat weight. The Lee 6 formula performed better than either Hadlock 3 or Lee 3 with the lowest random error. Fractional limb volumes involve a highly reproducible technique, with excellent correlation (intra-class coefficient >0.90) for both inter- and intra-observer reliability. The prevalence of estimated EFW measures within 10% error from the actual birth weight was 71.7% with the Hadlock 3 model and 95.0% with the Lee 6 model (p = 0.09)., Conclusion: Late assessment of 3D fetal limb volume in upper and lower extremities is not only useful for accurately predicting birth weight but is a useful marker for prediction of birth fat tissue weight., (© 2021 S. Karger AG, Basel.)

Introduction: The aim of this study was to obtain expert consensus on the content of a curriculum for learning chorionic villus sampling (CVS) and amniocentesis (AC) and the items of an assessment tool to evaluate CVS and AC competence., Methods: We used a 3-round iterative Delphi process. A steering committee supervised all processes. Seven international collaborators were identified to expand the breadth of the study internationally. The collaborators invited fetal medicine experts to participate as panelists. In the first round, the panelists suggested content for a CVS/AC curriculum and an assessment tool. The steering committee organized and condensed the suggested items and presented them to the panelists in round 2. In the second round, the panelists rated and commented on the suggested items. The results were processed by the steering committee and presented to the panelists in the third round, where final consensus was obtained. Consensus was defined as support by more than 80% of the panelists for an item., Results: Eighty-six experts agreed to participate in the study. The panelists represented 16 countries across 4 continents. The final list of curricular content included 12 theoretical and practical items. The final assessment tool included 11 items, systematically divided into 5 categories: pre-procedure, procedure, post-procedure, nontechnical skills, and overall performance. These items were provided with behavioral scale anchors to rate performance, and an entrustment scale was used for the final overall assessment., Conclusion: We established consensus among international fetal medicine experts on content to be included in a CVS/AC curriculum and on an assessment tool to evaluate CVS/AC skills. These results are important to help transition current training and assessment methods from a time- and volume-based approach to a competency-based approach which is a key step in improving patient safety and outcomes for the 2 most common invasive procedures in fetal medicine., (© 2021 S. Karger AG, Basel.)

Objective: The study aimed to investigate the association between placental growth factor (PlGF) and adverse obstetric outcomes in a mixed-risk cohort of pregnant women screened for preeclampsia (PE) in the first trimester., Methods: We included women with singleton pregnancies screened for PE between April 2014 and September 2016. Outcome data were retrieved from the New South Wales Perinatal Data Collection (NSW PDC) by linkage to the prenatal cohort. Adverse outcomes were defined as spontaneous preterm birth (sPTB) before 37-week gestation, birth weight (BW) below the 3rd centile, PE, gestational hypertension (GH), stillbirth, and neonatal death., Results: The cohort consisted of 11,758 women. PlGF multiple of the median (MoM) was significantly associated with maternal sociodemographic characteristics (particularly smoking status and parity) and all biomarkers used in the PE first trimester screening model (notably pregnancy-associated plasma protein A MoM and uterine artery pulsatility index [PI] MoM). Low levels of PlGF (<0.3 MoM and <0.5 MoM) were independently associated with sPTB, low BW, PE, GH, and a composite adverse pregnancy outcome score, with odds ratios between 1.81 and 4.44 on multivariable logistic regression analyses., Conclusions: Low PlGF MoM levels are independently associated with PE and a range of other adverse pregnancy outcomes. Inclusion of PlGF should be considered in future models screening for adverse pregnancy outcomes in the first trimester., (© 2021 S. Karger AG, Basel.)

Objective: Monochorionic diamniotic (MCDA) twins are at increased risk of adverse outcome due to unequal placental sharing and placental vascular communications between the fetal circulations. Most centres perform ultrasound examination every 2-3 weeks to identify these complications. Identifying a high-risk cohort of MCDA twins in the first trimester would allow more efficient surveillance. We have attempted to validate first-trimester ultrasound characteristics as predictive tools for twin-twin transfusion syndrome (TTTS) and selective intrauterine growth restriction (sIUGR) in MCDA twins., Material and Methods: This is a prospective cohort study including MCDA twins enrolled at the time of first-trimester combined screening. Differences in crown-rump length (CRL), nuchal translucency (NT) thickness, ductus venosus pulsatility index for veins (DV PIV), presence or absence of tricuspid regurgitation and right ventricular E/A ratio were assessed. Receiver operating characteristic (ROC) curves were used to assess the potential value of these measures as predictive tools for identifying a cohort of MCDA pregnancies at high risk of adverse pregnancy outcome., Results: Sixty-five MCDA pregnancies were included in the analysis. Nine (14%) developed TTTS, 17 (26%) developed sIUGR. The best predictive marker for TTTS was NT discordance of ≥20% (ROC AUC = 0.79; 95% CI 0.59-0.99). Combining measures did not improve performance (AUC = 0.80; 95% CI 0.62-0.99)., Conclusion: NT discordance was the most effective characteristic at predicting TTTS but still had a relatively poor positive predictive value (36%). Intertwin differences in CRL, DV PIV and E/A ratio were not predictive of subsequent pregnancy complications. None of these characteristics have sufficient efficacy to be used to triage MCDA twin pregnancies ongoing obstetric surveillance., (© 2020 S. Karger AG, Basel.)

Background: Preterm prelabour rupture of membranes (PPRoM) is commonly associated with preterm delivery and affects up to 3% of all pregnancies. It is associated with high rates of morbidity and mortality for the mother and the newborn., Objectives: To identify risk factors for PPRoM and develop a model for first-trimester prediction of risk of PPRoM., Methods: A retrospective analysis of a series of women who had first-trimester (11-13+6 weeks) screening for aneuploidy and pre-eclampsia and delivered in the same institution was performed. Univariate and multivariate logistic regression analyses were used to identify maternal and pregnancy factors and then develop a clinical prediction model for PPRoM., Results: 10,280 women were screened between April 2010 and October 2016. 144 (1.4%) had PPRoM. Maternal factors predictive of PPRoM included nulliparity (parous women, OR 0.53; 95% CI 0.4-0.8), pre-existing diabetes mellitus (DM) (Type 1 DM, OR 6.7; 95% CI 2.3-19.4, Type 2 DM, OR 5.3; 95% CI 1.6-18.3), maternal age group (p = 0.004), and BMI category (p = 0.012). Uterine artery pulsatility index (UAPI) and biochemical parameters (PAPP-A, free βHCG) did not reach statistical significance. The predictive model had moderate efficacy with an area under the ROC curve of 0.67., Conclusions: Several maternal characteristics collected during first-trimester screening predict PPRoM. Biomarkers currently measured during first-trimester screening (PAPP-A, βHCG, and UAPI) do not predict PPRoM. Whilst a predictive model can be generated with information currently collected at 11-13+6 weeks, this has only modest screening performance. First-trimester screening provides a structured framework where other predictors could improve model performance, and future studies should focus on the addition of other risk factors and biomarkers that may improve screening efficacy., (© 2020 S. Karger AG, Basel.)

Aim: To examine the performance of the combined First Trimester Screening (cFTS) algorithm when outliers of 4 risk parameters (maternal age, nuchal translucency (NT) thickness, PAPP-A and β-hCG) were included in the classification of "high-risk"., Methods: A retrospective analysis of singleton pregnancies undergoing cFTS between 2008 and 2011 in Denmark. Abnormal karyotypes were classified as trisomy 21 (T21), trisomy 13 (T13) and trisomy 18 (T18), sex chromosome aberrations and atypical abnormal karyotypes., Results: cFTS was completed in 193,638 pregnancies. In 10,205 (5.3%) cases, cytogenetic or molecular analysis was performed pre- or postnatally. An abnormal karyotype was seen in 1,122 (11.0%). The algorithm identified 87% of T21, 80% of T13, 75% of T18, 79% of sex chromosome aberrations and 35% of atypical abnormal karyotypes. Additional classification of a single risk parameter outlier (low PAPP-A or free β-hCG (< 0.2 MoMs), high β-hCG (≥5.0 MoMs), maternal age ≥45 years or NT ≥3.5 mm) as being at high-risk would have improved detection rates to 88, 80, 81, 81 and 37% respectively. The screen positive rate increased from 4.4 to 4.8%., Discussion: Addition of outliers of the 4 parameters used in cFTS algorithm will lead to a statistically significant increase in detection rates for chromosomal abnormality., (© 2018 S. Karger AG, Basel.)

Objectives: To determine which 3-D techniques are most effective for "real time" prenatal ultrasound assessment of the corpus callosum and cerebellar vermis., Methods: A prospective study involving 100 consecutive normal singleton pregnancies attending routine anomaly scan at 19-23 weeks' gestation. Midsagittal structures of the fetal brain were assessed using six different methods of 3-D image acquisition and three post-processing techniques. The quality of the resulting images were then assessed and scored by a second operator. The significance of the difference between various techniques was assessed using the Friedman test., Results: The best method for visualization of both corpus callosum and cerebellar vermis in one image involved 3-D acquisition in a sagittal plane through the sagittal suture with manipulated 3-D OVIX™ (Oblique View eXtended Imaging) reconstruction. Five other methods scored closely and were not significantly different; all were based on 3-D acquisition in the sagittal plane through either sagittal suture or anterior fontanel., Conclusions: We have applied described techniques for 3-D central nervous system volume acquisition and have shown that the best method of assessment, allowing assessment of both the corpus callosum and the cerebellar vermis, involves midsagittal acquisition through the sagittal suture with 3-D OVIX reconstruction. This technique can be applied successfully in 83% of cases., (© 2017 S. Karger AG, Basel.)

Chromosomal aneuploidy is responsible for a significant proportion of pregnancy failures, whether conceived naturally or through in vitro fertilization (IVF). In an effort to improve the success rate of IVF, screening embryos for aneuploidy - or pre-implantation genetic screening (PGS) - has been proposed as a means of ensuring only euploid embryos are selected for transfer. Early PGS approaches were based on fluorescence in situ hybridization testing, and have been shown not to improve live birth rates. Recent developments in genetic testing technologies - such as next-generation sequencing and quantitative polymerase chain reaction, coupled with embryo biopsy at the blastocyst stage - have shown promise in improving IVF outcomes, but they remain to be validated in adequately powered, prospective randomized trials. The extent to which IVF with PGS lowers the a priori risk of aneuploidy in ongoing pregnancies so conceived has been poorly described, rendering it difficult to incorporate the potential benefit of PGS into existing prenatal aneuploidy screening regimens such as cell-free DNA testing or conventional combined nuchal translucency and maternal biochemistry assessment. Further data on the sensitivity and specificity of various forms of molecular PGS testing would improve our understanding of the effectiveness and accuracy of these technologies. This, in addition to further research into methods of risk combination and assessment, would allow us to help our patients make better- informed decisions about whether or not to proceed with invasive diagnostic tests., (© 2016 S. Karger AG, Basel.)

Objective: The aim of this study was to determine whether morphology and measurement of the umbilical cord could be accurately assessed at the time of the 11- to 13(+6)-week scan., Methods: We conducted a prospective study of 100 consecutive women with singleton pregnancies at 11-13(+6) weeks' gestation who were seen for routine aneuploidy screening. Transabdominal ultrasound scans were performed, and the distance between two adjacent coils of the umbilical artery was measured in a free loop of umbilical cord. The antenatal umbilical coiling index (aUCI) was calculated as the inverse of this measurement (aUCI = 1/intercoil distance in cm). The maximum diameter of the umbilical vein was measured. Umbilical venous blood flow velocity was obtained using standard Doppler technique. Interobserver variability was assessed. A subjective assessment of the cord was performed using the Sepulveda system of classification to compare the reproducibility of the observations between two observers., Results: The intended measurements could be obtained in all cases. The aUCI was found to decrease with advancing gestation, while the umbilical venous diameter increased with gestation. The umbilical venous blood flow velocity also increased with gestation. Interobserver consistency in the objective measurement of the aUCI was poor (kappa 0.146). However, the Sepulveda classification system was found to be applicable and reproducible at this period of gestation (kappa 0.601)., Conclusions: Umbilical cord morphology can be consistently studied in the first trimester. A subjective method of evaluation of the morphology may be a more reproducible technique until measurement strategies are refined and operator experience developed., (© 2015 S. Karger AG, Basel.)

Introduction: Extremes of fetal growth are associated with increased perinatal mortality and morbidity and a higher prevalence of cardiovascular disease, obesity and diabetes in later life. We aimed to identify changes in placental gene expression in pregnancies with evidence of growth dysfunction and candidate genes that may be used to identify abnormal patterns of growth prior to delivery., Methods: Growth-restricted (n = 4), macrosomic (n = 6) and normal term (n = 5) placentas were selected from a banked series (n = 200) collected immediately after caesarean section. RNA was extracted prior to microarray analysis using Affymetrix HG-U219 arrays to determine variation in gene expression. Genes of interest were confirmed using qRT-PCR., Results: 338 genes in the growth-restricted and 41 genes in the macrosomic group were identified to be significantly dysregulated (>2-fold change; p < 0.05). CPXM2 and CLDN1 were upregulated and TXNDC5 and LRP2 downregulated in fetal growth restriction. In macrosomia, PHLDB2 and CLDN1 were upregulated and LEP and GCH1 were downregulated., Discussion: Dysfunctional growth is associated with differential placental gene expression and affects genes with a whole spectrum of developmental and cellular functions. Better elucidation of these pathways may allow the development of biomarkers to identify growth abnormalities and effective prenatal intervention.

Introduction: Standardization of first-trimester nuchal translucency (NT) image acquisition is crucial to the success of screening for Down syndrome. Rigorous audit of operator performance and constructive feedback from assessors maintain standards. This process relies on good inter-rater agreement on image assessment. We describe the Australian approach to NT image assessment and evaluate the impact of a targeted intervention on inter-rater agreement., Methods: Between 2002 and 2008 a group of experienced practitioners met nine times to compare their assessment of a series of NT images. Each assessor had previously scored the images according to a system described in 2002. Inter-rater agreement was evaluated before and after an intervention where the assessors were required to refer to a detailed resource manual designed to reduce the subjectivity inherent in image assessment., Results: There was a statistical improvement in inter-rater agreement for all elements of image assessment (original scores and individual component scores) after the intervention, apart from horizontal fetal position. However, even after the intervention, inter-rater agreement levels generally remained moderate (kappa range: 0.14-0.58)., Conclusions: This study has shown that provision of detailed resource documentation to experienced assessors can significantly improve inter-rater agreement in all facets of NT image assessment. It also highlights areas of image assessment that require critical review. It is recommended that all audit bodies regularly review their inter-rater agreement to ensure consistent feedback to operators who submit images for expert peer review., (2011 S. Karger AG, Basel.)

At 10-14 weeks of gestation about 80% of fetuses with chromosomal defects have abnormal accumulation of subcutaneous fluid in the nuchal region that is visualized by ultrasonography as nuchal translucency. A possible cause for this translucency is cardiac dysfunction due to the associated defects in the heart and great arteries. The aim of this study was to investigate whether in cardiac tissue from trisomic fetuses, compared to normals, there is an alteration in the steady state levels of expression of the genes encoding sarcoplasmic reticulum calcium ATPase (calcium ATPase), which is known to be downregulated in postnatal heart failure. After termination of pregnancy at 10-18 weeks of gestation, mRNA was extracted from cardiac tissue in 11 trisomy 21 and 4 trisomy 18 fetuses. Densitometric analysis of the Northern and slot blots was used to determine the steady state levels of expression of calcium ATPase and the values from the trisomic fetuses were compared to those of 30 normal controls at 10-18 weeks. Calcium ATPase gene expression did not change significantly with gestation at 10-18 weeks. In trisomic fetuses there was no significant decrease in calcium ATPase expression and expression levels of calcium ATPase were not related to increased nuchal translucency. However, the levels expressed in fetuses are already very low and cardiac dysfunction as a potential etiological factor cannot be excluded.

In trisomy 18, echocardiographic studies of affected neonates and pathological studies of stillbirths and infants have demonstrated a high incidence of cardiac defects. Fetal trisomy 18 can now be detected at 11-14 weeks of gestation, providing the opportunity to examine the incidence of cardiac defects at this gestational age. In 19 fetuses with trisomy 18 pathological examination of heart and great vessels was carried out after termination of pregnancy at 11-14 weeks of gestation. The abnormal karyotype was diagnosed by chorion villus sampling in pregnancies with increased fetal nuchal translucency thickness. All 19 fetuses had cardiac defects, and the commonest were ventricular septal defects in 16 (84%) and valvular abnormalities in 16 (84%). In 14 of the 16 cases with valvular abnormalities more than one valve was affected. The great vessels were available for examination in 18 of the 19 cases, and in 10 there was a hypoplastic aortic isthmus or pulmonary trunk. In 6 (32%) cases there was persistence of the left superior vena cava. In 1st-trimester fetuses with trisomy 18, the frequency of perimembranous ventricular septal defects and valvular abnormalities is similar to that in affected neonates. Haemodynamic changes due to the valvular abnormalities, especially imperforate valves, and hypoplasia of the great vessels may be the underlying mechanisms for the increased nuchal translucency of trisomic fetuses. Persistence of the left superior vena cava may result from venous congestion of head and neck.