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Background: LGALS13 (placental protein 13 [PP13]) promoter DNA polymorphisms was evaluated in predicting preeclampsia (PE), given PP13's effects on hypotension, angiogenesis, and immune tolerance.Methods: First-trimester plasma samples (49 term and 18 intermediate) of PE cases matched with 196 controls were collected from King's College Hospital, London, repository. Cell-free DNA was extracted and the LGALS13 exons were sequenced after PCR amplification. Expression of LGALS13 promoter reporter constructs was determined in BeWo trophoblast-like cells with luciferase assays. Adjusted odds ratio (OR) was calculated for the A/A genotype combined with maternal risk factors.Results: The A/A, A/C, and C/C genotypes in the -98 promoter position were in Hardy-Weinberg equilibrium in the control but not in the PE group (p < 0.036). The dominant A/A genotype had higher frequency in the PE group (p < 0.001). The A/C and C/C genotypes protected from PE (p < 0.032). The ORs to develop term and all PE, calculated for the A/A genotype, previous PE, body mass index (BMI) >35, black ethnicity, and maternal age >40 were 15.6 and 11.0, respectively (p < 0.001). In luciferase assays, the "-98A" promoter variant had lower expression than the "-98C" variant in non-differentiated (-13%, p = 0.04) and differentiated (-26%, p < 0.001) BeWo cells. Forskolin-induced differentiation led to a larger expression increase in the "-98C" variant than in the "-98A" variant (4.55-fold vs. 3.85-fold, p < 0.001).Conclusion: Lower LGALS13 (PP13) expression with the "A" nucleotide in the -98 promoter region position (compared to "C") and high OR calculated for the A/A genotype in the -98A/C promoter region position, history of previous PE, BMI >35, advanced maternal age >40, and black ethnicity could serve to aid in PE prediction in the first trimester. [ABSTRACT FROM AUTHOR]

Objectives: To assess Congo red urine test in the first trimester for preeclampsia (PE) prediction.Sample: A Congo red test was developed with a cohort of 81 pregnant women in Bnai Zion hospital, Israel, at 26-41 weeks of gestation (12 PE cases). The test was then applied to a first-trimester cohort of 642 women at King's College Hospital, UK (105 subsequently developed PE, 21 early, i.e., <34 weeks; 537 controls).Methods: Urine samples were spotted onto nitrocellulose membranes, stained with Congo red, de-stained, dried and quantified with imager and densitometry.Results: At PE signs and symptoms, the detection rate (DR) was 93% and the false-positive rate (FPR) 4%. However, with first-trimester urine samples, the DR was 33.3%, 16.1% and 20% for early, late and all PE cases, respectively, at 12.8% FPR. The odds ratio (OR) for PE by Congo red alone (including adjusted OR) was superior to body mass index and mean arterial blood pressure (MAP) but inferior to previous PE and black ethnicity. Combining all five parameters generated an adjusted OR of 13.92 for PE (p < 0.001).Conclusion: Congo red urine test at PE verifies the disorder. In the first trimester, it adds accuracy for PE prediction in obese, black women, who had previous PE and over-average MAP. [ABSTRACT FROM AUTHOR]

Objectives: To develop and validate a prediction model for gestational diabetes mellitus (GDM) at 11-13 weeks' gestation based on maternal characteristics and history and to compare its performance with the method recommended by the National Institute of Health and Care Excellence (NICE) and five other published prediction models. Methods: A predictive logistic regression model for GDM was developed from 1,827 cases (2.4%) who developed GDM and 73,334 unaffected controls. A 5-fold cross-validation study was performed to validate this model and to compare its performance with those of the NICE guidelines and the previously published models. Results: In the logistic regression model, maternal age, weight, height, racial origin, family history of diabetes, use of ovulation drugs, birth weight, and previous history of GDM were found to be significant predictors of GDM. In screening for GDM in the 5-fold cross-validation study, detection rates (DRs) were higher (p < 0.0001) for the proposed model (DR = 83.2%) than for the NICE guidelines (DR = 77.5%) for a false positive rate of approximately 40% (determined by NICE). The area under the receiver operating characteristic curve of the new model was higher (p < 0.0001) than that of the previous five models (0.823 vs. 0.688-786). Conclusions: Early effective screening for GDM can be achieved based on maternal characteristics and history. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Objective: To estimate the proportion of other chromosomal abnormalities that could be missed if combined testing was replaced by cell-free (cf) DNA testing as the method of screening for trisomies 21, 18 and 13.Methods: The prevalence of trisomies 21, 18 or 13, sex chromosome aneuploidies, triploidy and other chromosomal abnormalities was examined in pregnancies undergoing first-trimester combined screening and chorionic villus sampling (CVS).Results: In 1,831 clinically significant chromosomal abnormalities in pregnancies with combined risk for trisomies 21, 18 and 13≥1:100, the contribution of trisomies 21, 18 or 13, sex chromosome aneuploidies, triploidy and other chromosomal abnormalities at high risk of adverse outcome was 82.9, 8.2, 3.9 and 5.0%, respectively. Combined screening followed by CVS for risk≥1:10 and cfDNA testing for risk 1:11-1:2,500 could detect 97% of trisomy 21 and 98% of trisomies 18 and 13. Additionally, 86% of monosomy X, half of 47,XXY, 47,XYY or 47,XXX, half of other chromosomal abnormalities and one third of triploidies, which are currently detected by combined screening and CVS for risk≥1:100, could be detected.Conclusions: Screening by cfDNA testing, contingent on results of combined testing, improves detection of trisomies, but misses a few of the other chromosomal abnormalities detected by screening with the combined test. [ABSTRACT FROM AUTHOR]

Objective: To examine potential performance of screening for trisomies by cell-free (cf) DNA testing in maternal blood contingent on results of first-line testing by combinations of fetal translucency thickness (NT), fetal heart rate (FHR), ductus venosus pulsatility index (DV PIV), and serum-free β-human chorionic gonadotropin (β-hCG), pregnancy-associated plasma protein-A (PAPP-A), placental growth factor (PLGF) and α-fetoprotein (AFP).Methods: Performance was estimated for firstly, screening by cfDNA in all pregnancies and secondly, cfDNA testing contingent on results of first-line testing by combinations of ultrasound and biochemical markers.Results: In first-line screening by cfDNA testing, the detection rate for trisomy 21 and trisomies 18 or 13 would be 99 and 96%, respectively, after invasive testing in 1% of the population. In contingent screening, a detection rate of 98% for trisomy 21 and 96% for trisomy 18 or 13, at an invasive testing rate of 0.7%, can be achieved by carrying out cfDNA testing in about 35, 20 and 11% of cases identified by first-line screening with the combined test alone (age, NT, FHR, β-hCG, PAPP-A), the combined test plus PLGF and AFP and the combined test plus PLGF, AFP and DV PIV, respectively.Conclusions: Effective first-trimester screening for trisomies can be achieved by contingent screening incorporating biomarkers and cfDNA testing. [ABSTRACT FROM AUTHOR]

Objective: To examine the performance of screening for trisomies 21, 18 and 13 at 11-13 weeks' gestation using specific algorithms for these trisomies based on combinations of fetal nuchal translucency thickness (NT), fetal heart rate (FHR), ductus venosus pulsatility index for veins (DV PIV), and serum free β-human chorionic gonadotropin (β-hCG), pregnancy-associated plasma protein A (PAPP-A), placental growth factor (PLGF) and α-fetoprotein (AFP). Methods: Model-based estimates of screening performance were produced for the distribution of maternal ages in England and Wales in 2011, and prospectively collected data on fetal NT, FHR, DV PIV, β-hCG, PAPP-A, PLGF and AFP from singleton pregnancies undergoing aneuploidy screening. Results: In screening by NT, FHR, free β-hCG and PAPP-A, using specific algorithms for trisomy 21 and trisomies 18 and 13 at the risk cutoff of 1:100, the estimated detection rate (DR) was 87.0% for trisomy 21 and 91.8% for trisomies 18 and 13, at a false-positive rate (FPR) of 2.2%. Addition of PLGF, AFP and DV PIV increased the DR to 93.3% for trisomy 21 and 95.4% for trisomies 18 and 13 and reduced the FPR to 1.3%. Conclusions: Effective screening for trisomies can be achieved using specific algorithms based on NT, FHR, DV PIV, β-hCG, PAPP-A, PLGF and AFP. © 2013 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Objective: To examine the performance of chromosome-selective sequencing of cell-free (cf) DNA in maternal blood for assessment of fetal sex chromosome aneuploidies. Methods: This was a case-control study of 177 stored maternal plasma samples, obtained before fetal karyotyping at 11-13 weeks of gestation, from 59 singleton pregnancies with fetal sex chromosome aneuploidies (45,X, n = 49; 47,XXX, n = 6; 47,XXY, n = 1; 47,XYY, n = 3) and 118 with euploid fetuses (46,XY, n = 59; 46,XX, n = 59). Digital analysis of selected regions (DANSR™) on chromosomes 21, 18, 13, X and Y was performed and the fetal-fraction optimized risk of trisomy evaluation (FORTE™) algorithm was used to estimate the risk for non-disomic genotypes. Performance was calculated at a risk cut-off of 1:100. Results: Analysis of cfDNA provided risk scores for 172 (97.2%) samples; 4 samples (45,X, n = 2; 46,XY, n = 1; 46,XX, n = 1) had an insufficient fetal cfDNA fraction for reliable testing and 1 case (47,XXX) failed laboratory quality control metrics. The classification was correct in 43 (91.5%) of 47 cases of 45,X, all 5 of 47,XXX, 1 of 47,XXY and 3 of 47,XYY. There were no false-positive results for monosomy X. Discussion: Analysis of cfDNA by chromosome-selective sequencing can correctly classify fetal sex chromosome aneuploidy with reasonably high sensitivity. © 2013 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Objectives: To determine maternal characteristics affecting uterine artery pulsatility index (PI) in normal pregnancies at 20-24 weeks' gestation and examine in pregnancies with preeclampsia (PE) the relation between uterine artery PI multiple of the median (MoM) and severity of disease. Methods: Uterine artery PI was measured at 20-24 weeks in 50,490 singleton pregnancies, including 1,442 (2.9%) that developed PE. Uterine artery PI was expressed as MoM after adjustment for maternal characteristics and corrected for adverse pregnancy outcomes. In PE, the correlation between uterine artery PI MoM with gestational age at delivery and birth weight Z-score was determined. Results: In the normal group there were significant independent contributions to uterine artery PI from gestational age, racial origin and prior history of PE, and/or small for gestational age (SGA). In the PE group, there was an inverse significant association between uterine artery PI MoM and both gestational age at delivery and birth weight Z-score (p < 0.0001). Uterine artery PI was above the 95th percentile (1.509 MoM) in 72.7, 36.1 and 14.9% of cases of PE requiring delivery at <34, 34-37 and ≥38 weeks, respectively, and the percentages for PE with SGA were 80.2, 55.6 and 37.4%. Conclusions: In a normal pregnancy, uterine artery PI is affected by maternal characteristics, and in PE, uterine artery PI MoM is related to the severity of the disease. © 2013 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Objective: To examine the possible relationship between maternal and fetal characteristics and pregnancy outcomes on fetal and maternal cell-free (cf) DNA in maternal plasma at 11-13 weeks' gestation. Methods: cfDNA was extracted from maternal plasma of 1,949 singleton pregnancies and chromosome-selective sequencing was used to determine the proportion of cfDNA and total cfDNA counts which was of fetal and maternal origin. Multivariate regression analysis was used to determine whether specific maternal and fetal characteristics and pregnancy complications, such as preeclampsia (PE), early spontaneous preterm birth (SPB) and delivery of small for gestational age (SGA) neonates, were significant predictors of fetal and maternal cfDNA in maternal plasma. Results: The fetal and maternal cfDNA plasma concentration increased with serum pregnancy-associated plasma protein-A and free β-human chorionic gonadotropin level, was higher in women of Afro-Caribbean and East-Asian racial origin than in Caucasians, and lower in smokers, but it was not significantly altered in pregnancies complicated by PE, SPB or SGA. The fetal cfDNA level was inversely related to maternal weight and uterine artery pulsatility index, and maternal cfDNA increased with maternal weight. Conclusions: The fetal and maternal cfDNA level in maternal plasma is affected by maternal and fetal characteristics, but it is not altered in pregnancy complications. Copyright © 2013 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Objective: To investigate the potential value of maternal serum concentration of soluble endoglin (sEng) at 30-33 weeks' gestation in the prediction of preeclampsia (PE) developing at or after 34 weeks. Methods: Serum sEng was measured at 11-13 and at 30-33 weeks' gestation in a case-control study of 50 cases that developed PE at or after 34 weeks and 250 unaffected controls. Regression analysis was used to determine which of the factors amongst the maternal characteristics were significant predictors of first- and third-trimester log10 sEng in the control group. The measured values of sEng were converted into multiples of the unaffected median (MoM) and the MoM values in the PE and controls were compared. Results: The median sEng MoM at 30-33 weeks was significantly higher in the PE group (1.39, IQR 0.94-2.18) than in the controls (0.95, IQR 0.77-1.19), but at 11-13 weeks there was no significant difference between the groups. In screening by a combination of maternal characteristics and third-trimester sEng, the detection rates of intermediate- and late-PE, at a false-positive rate of 10%, were 64.3 and 50.0%, respectively. Conclusion: Screening by maternal characteristics and sEng at 30-33 weeks could identify most pregnancies that will subsequently develop PE. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Objective: To develop models for prediction of preeclampsia (PE) based on maternal characteristics, biophysical and biochemical markers at 11-13 weeks' gestation in which the gestation at the time of delivery for PE is treated as a continuous variable. Methods: This was a screening study of singleton pregnancies at 11-13 weeks including 1,426 (2.4%) that subsequently developed PE and 57,458 that were unaffected by PE. We developed a survival time model for the time of delivery for PE in which Bayes' theorem was used to combine the prior information from maternal characteristics with uterine artery pulsatility index (PI), mean arterial pressure (MAP), serum pregnancy-associated plasma protein-A (PAPP-A) and placental growth factor (PLGF) multiple of the median (MoM) values. Results: In pregnancies with PE, there was a linear correlation between MoM values of uterine artery PI, MAP, PAPP-A and PLGF with gestational age at delivery and therefore the deviation from normal was greater for early than late PE for all four biomarkers. Screening by maternal characteristics, biophysical and biochemical markers detected 96% of cases of PE requiring delivery before 34 weeks and 54% of all cases of PE at a fixed false-positive rate of 10%. Conclusions: A new model has been developed for effective first-trimester screening for PE. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Objective: To combine a specific algorithm for small for gestational age (SGA) without preeclampsia (PE) and another algorithm for PE in the prediction of SGA and PE. Methods: This was a screening study of singleton pregnancies at 11-13 weeks including 1,426 (2.3%) that subsequently developed PE, 3,168 (5.1%) that delivered SGA neonates and 57,458 that were unaffected by PE and SGA. We developed a prediction algorithm for SGA requiring delivery before 37 weeks' gestation (preterm-SGA) from maternal characteristics, uterine artery pulsatility index, mean arterial pressure, serum pregnancy-associated plasma protein-A and placental growth factor multiple of the median values. We then examined the performance of this algorithm individually and in combination with a previously reported algorithm for early-PE in the prediction of SGA and PE. Results: When screen positivity was defined by risk cutoff of 1:200 using the algorithm for early-PE and the risk cutoff of 1:150 using the algorithm for preterm-SGA, the false positive rate was 10.9% and the detection rates of early-PE, late-PE, preterm-SGA and term-SGA were 95.3, 45.6, 55.5 and 44.3%, respectively. Conclusions: Effective first-trimester screening for early-PE and preterm-SGA can be provided by the combined use of the specific algorithms. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Objective: To examine the role of second-trimester uterine artery Doppler in the prediction of stillbirths. Methods: Uterine artery pulsatility index (PI) was measured at 20-24 weeks' gestation in 65,819 singleton pregnancies. The PI was converted to multiples of median (MoM) and compared in live births and stillbirths. Regression analysis was used to determine the significance of association between log10 uterine artery PI MoM and gestational age (GA) at delivery in cases of stillbirths. Results: There were 306 (0.46%) stillbirths and in 159 (52.0%) of these there was pre-eclampsia (PE), placental abruption and/or birthweight below the 10th percentile (small for gestational age, SGA). In the stillbirths, the uterine artery PI MoM was significantly higher than in live births and was inversely associated with GA at delivery. The uterine artery PI MoM was above the 90th percentile in 80.6% of stillbirths with PE, abruption and/or SGA delivering at <32 weeks' gestation, in 41.9% at 33-36 weeks and in 34.3% at ≥37 weeks, and the respective percentages for stillbirths without PE, abruption or SGA were 15.8, 25.0 and 12.4%. Conclusion: Second-trimester uterine artery PI is effective in identifying early stillbirths in association with PE, abruption or SGA but not late deaths in the absence of PE, abruption or SGA. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Objective:To examine aortic systolic blood pressure (SBPAo), pulse wave velocity (PWV) and augmentation index (adjusted to a heart rate of 75 beats per minute, Alx-75) at 11-13 weeks' gestation in pregnancies delivering small for gestational age (SGA) neonates with and without preeclampsia (PE). Methods: At 11+0 to 13+6 weeks' gestation, maternal history was recorded and PWV, Alx-75, SBPAo, uterine artery pulsatility index (PI) and maternal serum pregnancy-associated plasma protein-A (PAPP-A) were measured. We compared women with (n = 337) and without (n = 48) PE that delivered SGA neonates with unaffected controls (n = 6,429). Results: In the SGA group without PE, compared to unaffected controls, there was no significant difference in Alx-75 (1.03 vs. 1.00 multiple of the median, MoM), PWV (0.98 vs. 1.00 MoM) or SBPAo (1.01 vs. 1.00 MoM), but uterine artery PI was increased (1.10 vs. 1.00 MoM) and PAPP-A decreased (0.85 vs. 1.00 MoM). In SGA with PE, compared to unaffected controls, there was increased Alx-75 (1.13 vs. 1.00 MoM), SBPAo (1.09 vs. 1.00 MoM), uterine artery PI (1.40 vs. 1.00 MoM) and decreased PAPP-A (0.72 vs. 1.00 MoM), but no significant difference in PWV (1.05 vs. 1.00 MoM). Conclusion: In pregnancies with SGA neonates, impaired placentation is reflected in low PAPP-A and high uterine artery PI at 11-13 weeks' gestation. In the SGA group with PE, but not in those without PE, there is increased SBPAo and Alx-75. [ABSTRACT FROM AUTHOR]

Objective: To establish a normal range of birthweight with gestational age (GA) at delivery and examine the contribution of maternal characteristics in defining growth restriction in stillbirths. Methods: In 69,895 normal singleton pregnancies, regression analysis was used to determine the association of birthweight with GA and maternal characteristics. The proportion of 290 stillbirths classified as small for GA depending on inclusion or exclusion of maternal characteristics was determined. Results: In normal pregnancies, there was a polynomial association between birthweight and GA. Birthweight increased with maternal weight, height and parity and was lower in Africans and South Asians than in Caucasians. Birthweight for GA was reduced in antepartum stillbirths (n = 243; p < 0.0001) but not in intrapartum stillbirths (n = 47; p = 0.334). There was no significant difference in the proportion of antepartum stillbirths with birthweight below the 10th percentile when birthweight was corrected for GA only compared to correction for GA and maternal characteristics (53.1 vs. 54.3%). The birthweight was below the 10th percentile in 71.8% of antepartum stillbirths at <32 weeks' gestation, in 47.2% at 33-36 weeks and in 31.5% at ≥37 weeks. Conclusion: Correction of birthweight for maternal characteristics does not alter the proportion of stillbirths that are small for GA. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Objective: It was the aim of this study to develop models for the prediction of preeclampsia (PE) based on maternal characteristics and biophysical markers at 11-13 weeks' gestation in which gestation at the time of delivery for PE is treated as a continuous variable. Methods: This was a screening study of singleton pregnancies at 11-13 weeks including 1,426 (2.4%) cases that subsequently developed PE and 57,458 cases that were unaffected by PE. We developed a survival time model for the time of delivery for PE in which Bayes' theorem was used to combine the prior information from maternal characteristics with the uterine artery pulsatility index (PI) and the mean arterial pressure (MAP), using multiple of the median values. Results: The risk for PE increased with maternal age, weight, Afro-Caribbean and South Asian racial origin, previous pregnancy with PE, conception by in vitro fertilization and a medical history of chronic hypertension, type 2 diabetes mellitus as well as systemic lupus erythematosus or antiphospholipid syndrome. In pregnancies with PE, there was an inverse correlation between multiple of the median values of the uterine artery PI and MAP with gestational age at delivery. Screening by maternal characteristics, uterine artery PI and MAP detected 90% of PE cases requiring delivery before 34 weeks and 57% of all PE cases at a fixed false-positive rate of 10%. Conclusions: A new model has been developed for effective first-trimester screening for PE. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Objective: In women with established pre-eclampsia and gestational diabetes there is an increase in central aortic systolic blood pressure (SBPAo), pulse wave velocity (PWV) and augmentation index (AIx), which are measures of arterial stiffness. The aim of this study was to establish normal ranges for PWV, AIx and SBPAo at 11-13 weeks' gestation and to examine the maternal characteristics which affect these parameters. Methods: This was a prospective study in singleton pregnancies at 11+0-13+6 weeks' gestation. Maternal history and characteristics were recorded and PWV, AIx and SBPAo were measured. Multiple regression analysis was used to examine which of the maternal characteristics provided a significant contribution in the prediction of Alx-75, PWV and SBPAo. Results: In normal pregnancies PWV, AIx-75 and SBPAo were related to certain maternal characteristics, including increase with maternal age for AIx-75 and PWV, decrease with maternal height for AIx-75 and increase with maternal weight for PWV and SBPAo and decrease for AIx (p < 0.0001). The median, 5th, 10th, 90th and 95th percentiles for AIx-75 MoM (multiple of the unaffected median), PWV MoM and SBPAo MoM were 1.00, 0.72, 0.79, 1.34 and 1.48; 1.00, 0.77, 0.82, 1.24 and 1.33; and 1.00, 0.86, 0.88, 1.15 and 1.20, respectively. Conclusions: This study provides normal ranges for PWV, AIx and SBPAo at 11-13 weeks' gestation and defines the maternal characteristics which affect these vascular parameters. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Objective: To assess the value of ductus venosus pulsatility index for veins (DV PIV) in screening for aneuploidies at 11-13 weeks' gestation. Methods: Fetal DV PIV was measured in singleton pregnancies undergoing first-trimester screening for aneuploidies. In euploid (n = 44,756) and aneuploid (202 cases of trisomy 21, 72 cases of trisomy 18 and 30 cases of trisomy 13) fetuses, DV PIV was best described by a mixture model of distributions. Performance of screening for aneuploidies by DV PIV alone and in combination with fetal nuchal translucency (NT) thickness and serum free β-hCG and PAPP-A was estimated. Results: In euploid pregnancies there was a bimodal distribution of DV PIV with a dominant crown-rump length (CRL)-dependent part, accounting for around 97% of cases in Caucasians and around 93% in Afro-Caribbeans, and a smaller CRL-independent distribution. In aneuploidies the dominant part was the CRL-independent distribution, which accounted for around 85% cases of trisomies 21 and 18 and 70% of cases of trisomy 13. In screening for trisomy 21 by maternal age, NT and biochemistry at a risk cutoff of 1 in 100, the detection rate was 89.7% and false positive rate was 2.74%; with addition of DV PIV, the values were 93.5 and 1.63%, respectively. Conclusions: Measurement of DV PIV improves the performance of first-trimester combined test for aneuploidies. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Objective: It was the aim of this study to examine the possible effects of maternal and fetal characteristics on the fetal fraction in maternal plasma cell-free DNA (cfDNA) at 11-13 weeks' gestation. Methods: In a nested case-control study, cfDNA was extracted from maternal plasma obtained before chorionic villous sampling from 300 euploid, 50 trisomy 21 and 50 trisomy 18 pregnancies at 11-13 weeks' gestation. Chromosome-selective sequencing of maternal cfDNA non-polymorphic and polymorphic loci, where fetal alleles differ from maternal alleles, was used to determine the proportion of DNA which is of fetal origin. Multivariate regression analysis was used to determine which of the factors amongst maternal weight, racial origin, smoking status, plasma storage time, serum pregnancy-associated plasma protein (PAPP)-A and free β-subunit of human chorionic gonadotropin (β-hCG), fetal crown-rump length, nuchal translucency thickness, gender and karyotype were significant predictors of the fetal fraction. Results: Significant independent prediction of fetal fraction was provided by maternal weight, serum PAPP-A and serum free β-hCG multiples of the median, but not by other maternal characteristics, fetal karyotype, crown-rump length or nuchal translucency thickness. Fetal fraction increased with serum metabolite levels and decreased with maternal weight. Conclusions: The fetal fraction in maternal plasma cfDNA increases with serum PAPP-A and free β-hCG and decreases with maternal weight. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Objective: It was the aim of this study to examine the potential value of cervical length at 11-13 weeks' gestation in the prediction of spontaneous preterm delivery. Methods: This was a screening study for spontaneous preterm delivery in singleton pregnancies from cervical length measured by transvaginal ultrasound at 11-13 weeks' gestation. The performance of screening for preterm delivery by cervical length alone and with maternal characteristics was estimated. Results: In the 9,974 pregnancies included in the study, spontaneous delivery before 34 weeks occurred in 104 (1.0%) cases. Multivariate regression analysis in the term delivery group demonstrated that for the log10 cervical length, significant independent contributions were provided by fetal crown-rump length, maternal height, age, racial origin and parity. The median cervical length multiple of the median (MoM), corrected for maternal characteristics, was significantly lower in the preterm (0.892 MoM, 95% CI 0.829-0.945) than in the term delivery group (0.994 MoM, 95% CI 0.919-1.082; p < 0.0001). In screening by a combination of maternal characteristics and cervical length, the estimated detection rate of preterm delivery was 54.8% (95% CI 44.7-64.6), at a false-positive rate of 10%. Conclusions: Effective first-trimester screening for spontaneous early preterm delivery can be provided by a combination of maternal characteristics and cervical length. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Objective: To investigate whether measurement of maternal serum placental growth factor (PLGF) can improve the performance of first-trimester combined screening for trisomy-21 by fetal nuchal translucency (NT) thickness and serum free β-human chorionic gonadotropin (β-hCG) and PAPP-A. Methods: In singleton pregnancies attending for routine care, serum PLGF, free β-hCG and PAPP-A were measured at 8+0-13+6 weeks' gestation, and fetal NT was measured at 11+0-13+6 weeks. The population included 12,154 normal and 44 trisomy-21 pregnancies. We examined the effect of adding PLGF on the performance of screening by the combined test. Results: In the trisomy-21 pregnancies the median multiple of the normal median PLGF, adjusted for gestational age, maternal weight, racial origin, smoking status and method of conception, was significantly reduced (0.6070, 95% CI 0.5543-0.6648), and this did not change significantly with gestational age. Adding PLGF to combined testing with a risk cut-off of 1 in 100 reduced the false positive rate from 2.7% (95% CI 2.5-3.0) to 2.6% (95% CI 2.4-2.8) and increased the detection rate from 85% (95% CI 75-93) to 88% (95% CI 78-95). Conclusions: Inclusion of serum PLGF improves the performance of the first-trimester combined test in screening for trisomy-21. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Objectives: To identify the best protocol for measurement of mean arterial pressure (MAP) in early pregnancy for the prediction of preeclampsia (PE). Methods: This was a prospective study in singleton pregnancies attending for a routine hospital visit at 11-13 weeks' gestation when a minimum of four recordings of MAP were taken from each arm. The performance of screening for PE by different combinations of MAP was compared to the protocol of the National Heart Foundation of Australia (NHFA). Results: The MAP was measured in 587 (2.4%) cases that developed PE and in 22,900 that were unaffected by hypertensive disorders in pregnancy. The area under the receiver operating characteristic curve (AUROC) for prediction of PE by MAP as recommended by the NHFA protocol was 0.773 (95% CI 0.768-0.778). This AUROC was not significantly different from the AUROC obtained by the average MAP of the first three measurements from one arm (0.765, 95% CI 0.760-0.771) or the average of the first (0.766, 95% CI 0.760-0.771), the first two (0.771, 95% CI 0.766-0.777), or the first three measurements from the two arms (0.773, 95% CI 0.768-0.778). Conclusion: Performance of screening for PE by taking the average of a minimum of two measurements from both arms is comparable to the NHFA protocol. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Objective: To examine the effect of method of conception on adverse pregnancy outcome after the 11-13 weeks scan. Methods: Prospective screening study for adverse obstetric outcomes in women with singleton pregnancies and live fetus with no obvious defects at 11+0-13+6 weeks. The method of conception was recorded as spontaneous, in vitro fertilization (IVF) and assisted by ovulation induction (OI) drugs without IVF. Regression analysis was performed to examine the association between the method of conception and pregnancy outcome after adjustment for maternal characteristics. Results: In the study population of 41,577 pregnancies, conception was spontaneous in 40,261 (96.9%), by IVF in 634 (1.5%) and by OI in 682 (1.6%). In the pregnancies conceived by assisted reproductive technology, compared to spontaneous conceptions, there was a higher risk of stillbirth, pre-eclampsia, gestational hypertension, gestational diabetes mellitus, delivery of small for gestational age neonates and caesarean section. However, multiple regression analysis showed that after taking into account maternal characteristics, the only significant contributions of IVF were for pre-eclampsia and elective caesarean section and the contributions of OI were for miscarriage, spontaneous early preterm delivery and small for gestational age. Conclusions: Conception by IVF and OI is associated with increased risk for adverse pregnancy outcome. Copyright © 2011 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Introduction: To examine the prevalence and outcome of absent ductus venosus (DV) diagnosed at 11-13 weeks' gestation. Method: Prospective screening study for aneuploidies in 65,840 singleton pregnancies, including measurement of nuchal translucency (NT) thickness and examination of the DV. Prenatal findings and outcome of fetuses with absent DV were examined. Results: Absent DV was diagnosed in 26 cases giving a prevalence of 1 in 2,532. In 15 (57.7%) cases the NT was above the 95th centile for crown-rump length. In 11 (42.3%) cases, there was an aneuploidy, mainly Turner syndrome. The incidence of aneuploidies was 66.7% (10 of 15) for those with NT above the 95th centile and 9.1% (1 of 11) in those with normal NT (p = 0.015). In addition to the aneuploidies, there were 3 cases with other abnormalities, including one case each of Ebstein anomaly, Noonan syndrome and Pierre Robin sequence. In 9 of the 11 (81.8%) fetuses with NT below the 95th centile, absent DV was an isolated finding and the pregnancies resulted in healthy live births. Conclusion: The prognosis of fetuses with absent DV depends on the measurement of NT thickness, being poor if the NT is increased and good if the NT is normal. Copyright © 2011 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Introduction: To examine the prevalence and outcome of absent ductus venosus (DV) diagnosed at 11-13 weeks' gestation. Method: Prospective screening study for aneuploidies in 65,840 singleton pregnancies, including measurement of nuchal translucency (NT) thickness and examination of the DV. Prenatal findings and outcome of fetuses with absent DV were examined. Results: Absent DV was diagnosed in 26 cases giving a prevalence of 1 in 2,532. In 15 (57.7%) cases the NT was above the 95th centile for crown-rump length. In 11 (42.3%) cases, there was an aneuploidy, mainly Turner syndrome. The incidence of aneuploidies was 66.7% (10 of 15) for those with NT above the 95th centile and 9.1% (1 of 11) in those with normal NT (p = 0.015). In addition to the aneuploidies, there were 3 cases with other abnormalities, including one case each of Ebstein anomaly, Noonan syndrome and Pierre Robin sequence. In 9 of the 11 (81.8%) fetuses with NT below the 95th centile, absent DV was an isolated finding and the pregnancies resulted in healthy live births. Conclusion: The prognosis of fetuses with absent DV depends on the measurement of NT thickness, being poor if the NT is increased and good if the NT is normal. [ABSTRACT FROM AUTHOR]

Objective: To determine whether assessment of ductus venosus flow at 11-13 weeks' gestation improves the detection rate of cardiac defects achieved by screening with nuchal translucency (NT) thickness. Methods: Prospective first-trimester screening for aneuploidies, including measurement of fetal NT and assessment of ductus venosus flow. The performance of different combinations of increased fetal NT and abnormal blood flow in the ductus venosus in screening for major cardiac defects was examined. Results: The study population of euploid fetuses included 85 cases with major cardiac defects and 40,905 with no cardiac defects. The fetal NT was above the 95th and above the 99th centile in 30 (35.3%) and 18 (21.2%) of the fetuses with cardiac defects, respectively, and in 1,956 (4.8%) and 290 (0.7%) of those without cardiac defects, respectively. Reversed a-wave was observed in 24 (28.2%) of the fetuses with cardiac defects and in 856 (2.1%) of those with no cardiac defects. Specialist fetal echocardiography for cases with NT above the 99th centile and those with reversed a-wave, irrespective of NT, would detect 38.8% of major cardiac defects at an overall false- positive rate of 2.7%. Conclusions: Assessment of ductus venosus flow improves the performance of NT screening for cardiac defects. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Objective: To determine if combinations of maternal characteristics and measurements of parameters used in screening for aneuploidies at 11-13 weeks provide significant prediction of macrosomia. Method: Maternal characteristics, fetal nuchal translucency (NT), free β-human chorionic gonadotrophin (β-hCG) and pregnancy-associated plasma protein-A (PAPP-A) were recorded at 11+0-13+6 weeks in 36,743 singleton pregnancies. Regression analysis was used to determine if in predicting macrosomia significant contributions are provided by maternal factors, fetal NT, free β-hCG and PAPP-A. Results: The risk for macrosomia increased with maternal weight and height and was higher in parous women with previous delivery of a macrosomic baby and in those with diabetes mellitus; the risk was lower in women of African and South Asian racial origins, in cigarette smokers and in those with chronic hypertension. In the macrosomic group compared to the unaffected group there were higher Δ-NT (0.167 vs. 0.116 mm), free β-hCG (1.010 vs. 0.964 MoM) and PAPP-A (1.103 vs. 1.003 MoM). Prediction of macrosomia provided by maternal factors was significantly improved by fetal NT, free β-hCG and PAPP-A (34.4 vs. 33.1% at a false-positive rate of 10%). Conclusion: Prediction of macrosomia is provided in the first trimester of pregnancy by a combination of maternal characteristics and measurements of parameters used in screening for aneuploidies. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Objectives: To construct normal ranges for embryonic crown-rump length (CRL), heart rate (HR), gestational sac diameter (GSD) and yolk sac diameter (YSD) at 6-10 weeks of gestation. Methods: We examined 4,698 singleton pregnancies with ultrasound measurements of CRL, HR, GSD and YSD at 6-10 weeks and CRL at 11-13 weeks resulting in the live birth after 36 weeks of phenotypically normal neonates with birth weight above the 5th centile. Gestational age was derived from CRL at the 11- to 13-week scan using the formula of Robinson and Fleming. Regression analysis was used to establish normal ranges of CRL, fetal HR, GSD and YSD with gestation, and fetal HR, GSD and YSD with CRL. Results: At 6-10 weeks there were significant quadratic associations between CRL, GSD, YSD and gestation and between HR, GSD, YSD and CRL, and a cubic association between HR and gestation. The estimated gestation from CRL was the same as that of Robinson and Fleming for a CRL of 10.2-36.5 mm, but the formula of Robinson and Fleming underestimated the gestation by 1 day for a CRL 7.4-10.2 mm and this increased to 9 days for a CRL of 1 mm. Conclusion: This study established normal ranges for early pregnancy biometry. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Introduction: The aim of this study was to examine the potential effect of chorionic villus sampling (CVS) on placental perfusion by examining the change in uterine artery pulsatility index (PI) between the first and second trimesters of pregnancy. Materials and Methods: This was a prospective screening study for pregnancy complications which included measurement of uterine artery PI at 11+0 to 13+6 weeks and at 20+0 to 24+6 weeks of gestation. In women at increased risk for fetal aneuploidies, CVS was performed. Uterine artery PI in the first and second trimesters, and the change in PI between the two examinations were compared between the CVS and non-CVS groups. Results: The study population included 8,822 singleton pregnancies, in 308 of which CVS was performed. In the CVS group, compared to the non-CVS group, the median uterine artery PI before CVS, corrected for gestational age, was higher in both the first and second trimesters of pregnancy, but the change in PI between the two examinations was not significantly different (p = 0.789). Conclusion: The performance of CVS in the first trimester is unlikely to interfere with normal placentation. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]