Prediction of pre-eclampsia in twin pregnancy by maternal factors and biomarkers at 11-13 weeks' gestation: data from EVENTS trial.

OBJECTIVES: First, to validate a previously developed model for screening for pre-eclampsia (PE) by maternal characteristics and medical history in twin pregnancies; second, to compare the distributions of mean arterial pressure (MAP), uterine artery pulsatility index (UtA-PI), serum placental growth factor (PlGF) and serum pregnancy-associated plasma protein-A (PAPP-A) in twin pregnancies that delivered with PE to those in singleton pregnancies and to develop new models based on these results; and, third, to examine the predictive performance of these models in screening for PE with delivery at < 32 and < 37 weeks' gestation. METHODS: Two datasets of prospective non-intervention multicenter screening studies for PE in twin pregnancies at 11 + 0 to 13 + 6 weeks' gestation were used. The first dataset was from the EVENTS (Early vaginal progesterone for the preVention of spontaneous prEterm birth iN TwinS) trial and the second was from a previously reported study that examined the distributions of biomarkers in twin pregnancies. Maternal demographic characteristics and medical history from the EVENTS-trial dataset were used to assess the validity of risks from our previously developed model. The combined data from the first and second datasets were used to compare the distributional properties of log10 multiples of the median (MoM) values of UtA-PI, MAP, PlGF and PAPP-A in twin pregnancies that delivered with PE to those in singleton pregnancies and develop new models based on these results. The competing-risks model was used to estimate the individual patient-specific risks of delivery with PE at < 32 and < 37 weeks' gestation. Screening performance was measured by detection rates (DR) and areas under the receiver-operating-characteristics curve. RESULTS: The EVENTS-trial dataset comprised 1798 pregnancies, including 168 (9.3%) that developed PE. In the validation of the prior model based on maternal characteristics and medical history, calibration plots demonstrated very good agreement between the predicted risks and the observed incidence of PE (calibration slope and intercept for PE < 32 weeks were 0.827 and 0.009, respectively, and for PE < 37 weeks they were 0.942 and -0.207, respectively). In the combined data, there were 3938 pregnancies, including 339 (8.6%) that developed PE and 253 (6.4%) that delivered with PE at < 37 weeks' gestation. In twin pregnancies that delivered with PE, MAP, UtA-PI and PlGF were, at earlier gestational ages, more discriminative than in singleton pregnancies and at later gestational ages they were less so. For PAPP-A, there was little difference between PE and unaffected pregnancies. The best performance of screening for PE was achieved by a combination of maternal factors, MAP, UtA-PI and PlGF. In screening by maternal factors alone, the DR, at a 10% false-positive rate, was 30.6% for delivery with PE at < 32 weeks' gestation and this increased to 86.4% when screening by the combined test; the respective values for PE < 37 weeks were 24.9% and 41.1%. CONCLUSIONS: In the assessment of risk for PE in twin pregnancy, we can use the same prior model based on maternal characteristics and medical history as reported previously, but in the calculation of posterior risks it is necessary to use the new distributions of log10 MoM values of UtA-PI, MAP and PlGF according to gestational age at delivery with PE. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

New approach for estimating risk of miscarriage after chorionic villus sampling.

OBJECTIVE: To estimate the risk of miscarriage associated with chorionic villus sampling (CVS). METHODS: This was a retrospective cohort study of women attending for routine ultrasound examination at 11 + 0 to 13 + 6 weeks' gestation at one of eight fetal-medicine units in Spain, Belgium and Bulgaria, between July 2007 and June 2018. Two populations were included: (1) all singleton pregnancies undergoing first-trimester assessment at Hospital Clínico Universitario Virgen de la Arrixaca in Murcia, Spain, that did not have CVS (non-CVS group); and (2) all singleton pregnancies that underwent CVS following first-trimester assessment at one of the eight participating centers (CVS group). We excluded pregnancies diagnosed with genetic anomalies or major fetal defects before or after birth, those that resulted in termination and those that underwent amniocentesis later in pregnancy. We used propensity score (PS) matching analysis to estimate the association between CVS and miscarriage. We compared the risk of miscarriage of the CVS and non-CVS groups after PS matching (1:1 ratio). This procedure creates two comparable groups balancing the maternal and pregnancy characteristics that are associated with CVS, in a similar way to that in which randomization operates in a randomized clinical trial. RESULTS: The study population consisted of 22 250 pregnancies in the non-CVS group and 3613 in the CVS group. The incidence of miscarriage in the CVS group (2.1%; 77/3613) was significantly higher than that in the non-CVS group (0.9% (207/22 250); P < 0.0001). The PS algorithm matched 2122 CVS with 2122 non-CVS cases, of which 40 (1.9%) and 55 (2.6%) pregnancies in the CVS and non-CVS groups, respectively, resulted in a miscarriage (odds ratio (OR), 0.72 (95% CI, 0.48-1.10); P = 0.146). We found a significant interaction between the risk of miscarriage following CVS and the risk of aneuploidy, suggesting that the effect of CVS on the risk of miscarriage differs depending on background characteristics. Specifically, when the risk of aneuploidy is low, the risk of miscarriage after CVS increases (OR, 2.87 (95% CI, 1.13-7.30)) and when the aneuploidy risk is high, the risk of miscarriage after CVS is paradoxically reduced (OR, 0.47 (95% CI, 0.28-0.76)), presumably owing to prenatal diagnosis and termination of pregnancies with major aneuploidies that would otherwise have resulted in spontaneous miscarriage. For example, in a patient in whom the risk of aneuploidy is 1 in 1000 (0.1%), the risk of miscarriage after CVS will increase to 0.3% (0.2 percentage points higher). CONCLUSIONS: The risk of miscarriage in women undergoing CVS is about 1% higher than that in women who do not have CVS, although this excess risk is not solely attributed to the invasive procedure but, to some extent, to the demographic and pregnancy characteristics of the patients. After accounting for these risk factors and confining the analysis to low-risk pregnancies, CVS seems to increase the risk of miscarriage by about three times above the patient's background risk. Although this is a substantial increase in relative terms, in pregnancies without risk factors for miscarriage, the risk of miscarriage after CVS remains low and similar to, or slightly higher than, that in the general population. Copyright © 2020 ISUOG. Published by John Wiley & Sons Ltd.

Nuevo enfoque para estimar el riesgo de aborto después de una biopsia de vellosidades coriónicas OBJETIVO: Estimar el riesgo de aborto asociado con la biopsia de vellosidades coriónicas (BVC). MÉTODOS: Se trata de un estudio retrospectivo de cohorte de mujeres que acudieron a un examen ecográfico de rutina entre las 11+0 y las 13+6 semanas de gestación a una de entre un total de ocho centros de medicina fetal en España, Bélgica y Bulgaria, entre julio de 2007 y junio de 2018. En el estudio se incluyeron dos poblaciones: 1) todos los embarazos con feto único sometidos a evaluación del primer trimestre en el Hospital Clínico Universitario Virgen de la Arrixaca de Murcia (España), a las que no se les hizo una BVC (grupo no BVC); y 2) todos los embarazos con feto único sometidos a BVC tras la evaluación del primer trimestre en uno de los ocho centros participantes (grupo BVC). Se excluyeron los embarazos diagnosticados con anomalías genéticas o defectos fetales importantes antes o después del nacimiento, los que resultaron en una interrupción y los que más tarde se sometieron a amniocentesis durante el embarazo. Para estimar la relación entre la BVC y el aborto espontáneo se utilizó el pareamiento por puntaje de propensión (PPP). Se comparó el riesgo de aborto de los grupos BVC y no BVC después del pareamiento PPP (razón 1:1). Este procedimiento creó dos grupos comparables en los que las características de la madre y el embarazo que se asocian con la BVC estaban equilibradas, de manera similar a cómo funciona la aleatorización en un ensayo clínico aleatorizado. RESULTADOS: La población de estudio consistió en 22.250 embarazos en el grupo no BVC y 3.613 en el grupo BVC. La incidencia de abortos en el grupo BVC (2,1%; 77/3.613) fue significativamente mayor que en el grupo no BVC (0,9% (207/22.250); P<0,0001). El algoritmo del PPP emparejó 2.122 BVC con 2.122 casos no BVC, de los cuales 40 (1,9%) y 55 (2,6%) embarazos en los grupos BVC y no BVC, respectivamente, resultaron en un aborto espontáneo (razón de momios (RM), 0,72 (IC 95%, 0,48-1,10); P=0,146). Se encontró una interacción significativa entre el riesgo de aborto espontáneo después de una BVC y el riesgo de aneuploidía, lo que sugiere que el efecto de la BVC en el riesgo de aborto espontáneo difiere según las características del contexto. Concretamente, cuando el riesgo de aneuploidía es bajo, el riesgo de aborto después de una BVC aumenta (RM, 2,87 (IC 95%, 1,13-7,30)) y cuando el riesgo de aneuploidía es alto, paradójicamente el riesgo de aborto después de una BVC se reduce (RM, 0,47 (IC 95%, 0,28-0,76)), presumiblemente debido al diagnóstico prenatal y a la interrupción de embarazos con aneuploidías importantes que, de otro modo, hubieran provocado un aborto espontáneo. Por ejemplo, en una paciente para quien el riesgo de aneuploidía es de 1 entre 1000 (0,1%), el riesgo de aborto después de la BVC aumenta al 0,3% (0,2 puntos porcentuales más alto). CONCLUSIONES: El riesgo de aborto espontáneo en las mujeres que se someten a una BVC es aproximadamente un 1% mayor que el de las mujeres a las que no se les hace, aunque este exceso de riesgo no se atribuye únicamente al procedimiento agresivo sino, en cierta medida, a las características demográficas y del embarazo de cada paciente. Después de tener en cuenta estos factores de riesgo y limitar el análisis a los embarazos de bajo riesgo, la BVC parece triplicar aproximadamente el riesgo de aborto en comparación con el riesgo de fondo de la paciente. Aunque se trata de un aumento sustancial en términos relativos, en los embarazos sin factores de riesgo de aborto, después de una BVC el riesgo de aborto sigue siendo bajo y similar, o ligeramente superior, al de la población en general. Copyright © 2020 ISUOG. Published by John Wiley & Sons Ltd.

Screening for pre-eclampsia by maternal factors and biomarkers at 11-13 weeks' gestation.

OBJECTIVE: To examine the performance of screening for early, preterm and term pre-eclampsia (PE) at 11-13 weeks' gestation by maternal factors and combinations of mean arterial pressure (MAP), uterine artery (UtA) pulsatility index (PI), serum placental growth factor (PlGF) and serum pregnancy-associated plasma protein-A (PAPP-A). METHODS: The data for this study were derived from three previously reported prospective non-intervention screening studies at 11 + 0 to 13 + 6 weeks' gestation in a combined total of 61 174 singleton pregnancies, including 1770 (2.9%) that developed PE. Bayes' theorem was used to combine the prior distribution of gestational age at delivery with PE, obtained from maternal characteristics, with various combinations of biomarker multiples of the median (MoM) values to derive patient-specific risks of delivery with PE at < 37 weeks' gestation. The performance of such screening was estimated. RESULTS: In pregnancies that developed PE, compared to those without PE, the MoM values of UtA-PI and MAP were increased and those of PAPP-A and PlGF were decreased, and the deviation from normal was greater for early than late PE for all four biomarkers. Combined screening by maternal factors, UtA-PI, MAP and PlGF predicted 90% of early PE, 75% of preterm PE and 41% of term PE, at a screen-positive rate of 10%; inclusion of PAPP-A did not improve the performance of screening. The performance of screening depended on the racial origin of the women; on screening by a combination of maternal factors, MAP, UtA-PI and PlGF and using a risk cut-off of 1 in 100 for PE at < 37 weeks in Caucasian women, the screen-positive rate was 10% and detection rates for early, preterm and term PE were 88%, 69% and 40%, respectively. With the same method of screening and risk cut-off in women of Afro-Caribbean racial origin, the screen-positive rate was 34% and detection rates for early, preterm and term PE were 100%, 92% and 75%, respectively. CONCLUSION: Screening by maternal factors and biomarkers at 11-13 weeks' gestation can identify a high proportion of pregnancies that develop early and preterm PE. © 2018 Crown copyright. Ultrasound in Obstetrics & Gynecology © 2018 ISUOG.

Prediction and prevention of small-for-gestational-age neonates: evidence from SPREE and ASPRE.

OBJECTIVES: To examine the effect of first-trimester screening for pre-eclampsia (PE) on the prediction of delivering a small-for-gestational-age (SGA) neonate and the effect of prophylactic use of aspirin on the prevention of SGA. METHODS: The data for this study were derived from two multicenter studies. In SPREE, we investigated the performance of screening for PE by a combination of maternal characteristics and biomarkers at 11-13 weeks' gestation. In ASPRE, women with a singleton pregnancy identified by combined screening as being at high risk for preterm PE (> 1 in 100) participated in a trial of aspirin (150 mg/day from 11-14 until 36 weeks' gestation) compared to placebo. In this study, we used the data from the ASPRE trial to estimate the effect of aspirin on the incidence of SGA with birth weight < 10th , < 5th and < 3rd percentile for gestational age. We also used the data from SPREE to estimate the proportion of SGA in the pregnancies with a risk for preterm PE of > 1 in 100. RESULTS: In SPREE, screening for preterm PE by a combination of maternal factors, mean arterial pressure, uterine artery pulsatility index and serum placental growth factor identified a high-risk group that contained about 46% of SGA neonates < 10th percentile born at < 37 weeks' gestation (preterm) and 56% of those born at < 32 weeks (early); the overall screen-positive rate was 12.2% (2014 of 16 451 pregnancies). In the ASPRE trial, use of aspirin reduced the overall incidence of SGA < 10th percentile by about 40% in babies born at < 37 weeks' gestation and by about 70% in babies born at < 32 weeks; in babies born at ≥ 37 weeks, aspirin did not have a significant effect on incidence of SGA. The aspirin-related decrease in incidence of SGA was mainly due to its incidence decreasing in pregnancies with PE, for which the decrease was about 70% in babies born at < 37 weeks' gestation and about 90% in babies born at < 32 weeks. On the basis of these results, it was estimated that first-trimester screening for preterm PE and use of aspirin in the high-risk group would potentially reduce the incidence of preterm and early SGA by about 20% and 40%, respectively. CONCLUSION: First-trimester screening for PE by the combined test identifies a high proportion of cases of preterm SGA that can be prevented by the prophylactic use of aspirin. © 2018 Crown copyright. Ultrasound in Obstetrics & Gynecology © 2018 ISUOG.

ASPRE trial: incidence of preterm pre-eclampsia in patients fulfilling ACOG and NICE criteria according to risk by FMF algorithm.

OBJECTIVE: To report the incidence of preterm pre-eclampsia (PE) in women who are screen positive according to the criteria of the National Institute for Health and Care Excellence (NICE) and the American College of Obstetricians and Gynecologists (ACOG), and compare the incidence with that in those who are screen positive or screen negative by The Fetal Medicine Foundation (FMF) algorithm. METHODS: This was a secondary analysis of data from the ASPRE study. The study population consisted of women with singleton pregnancy who underwent prospective screening for preterm PE by means of the FMF algorithm, which combines maternal factors and biomarkers at 11-13 weeks' gestation. The incidence of preterm PE in women fulfilling the NICE and ACOG criteria was estimated; in these patients the incidence of preterm PE was then calculated in those who were screen negative relative to those who were screen positive by the FMF algorithm. RESULTS: A total of 34 573 women with singleton pregnancy delivering at ≥ 24 weeks' gestation underwent prospective screening for preterm PE, of which 239 (0.7%) cases developed preterm PE. At least one of the ACOG criteria was fulfilled in 22 287 (64.5%) pregnancies and the incidence of preterm PE was 0.97% (95% CI, 0.85-1.11%); in the subgroup that was screen positive by the FMF algorithm the incidence of preterm PE was 4.80% (95% CI, 4.14-5.55%), and in those that were screen negative it was 0.25% (95% CI, 0.18-0.33%), with a relative incidence in FMF screen negative to FMF screen positive of 0.051 (95% CI, 0.037-0.071). In 1392 (4.0%) pregnancies, at least one of the NICE high-risk criteria was fulfilled, and in this group the incidence of preterm PE was 5.17% (95% CI, 4.13-6.46%); in the subgroups of screen positive and screen negative by the FMF algorithm, the incidence of preterm PE was 8.71% (95% CI, 6.93-10.89%) and 0.65% (95% CI, 0.25-1.67%), respectively, and the relative incidence was 0.075 (95% CI, 0.028-0.205). In 2360 (6.8%) pregnancies fulfilling at least two of the NICE moderate-risk criteria, the incidence of preterm PE was 1.74% (95% CI, 1.28-2.35%); in the subgroups of screen positive and screen negative by the FMF algorithm the incidence was 4.91% (95% CI, 3.54-6.79%) and 0.42% (95% CI, 0.20-0.86%), respectively, and the relative incidence was 0.085 (95% CI, 0.038-0.192). CONCLUSION: In women who are screen positive for preterm PE by the ACOG or NICE criteria but screen negative by the FMF algorithm, the risk of preterm PE is reduced to within or below background levels. The results provide further evidence to support the personalized risk-based screening method that combines maternal factors and biomarkers. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

ASPRE trial: performance of screening for preterm pre-eclampsia.

OBJECTIVE: To examine the performance of screening for preterm and term pre-eclampsia (PE) in the study population participating in the ASPRE (Combined Multimarker Screening and Randomized Patient Treatment with Aspirin for Evidence-Based Preeclampsia Prevention) trial. METHODS: This was a prospective first-trimester multicenter study on screening for preterm PE in 26 941 singleton pregnancies by means of an algorithm that combines maternal factors, mean arterial pressure, uterine artery pulsatility index and maternal serum pregnancy-associated plasma protein-A and placental growth factor at 11-13 weeks' gestation. Eligible women with an estimated risk for preterm PE of > 1 in 100 were invited to participate in a double-blind trial of aspirin (150 mg per day) vs placebo from 11-14 until 36 weeks' gestation, which showed that, in the aspirin group, the incidence of preterm PE was reduced by 62%. In the screened population, the detection rates (DRs) and false-positive rates (FPRs) for delivery with PE < 37 and ≥ 37 weeks were estimated after adjustment for the effect of aspirin in those receiving this treatment. We excluded 1144 (4.2%) pregnancies because of loss to follow-up or study withdrawal (n = 716), miscarriage (n = 243) or termination (n = 185). RESULTS: The study population of 25 797 pregnancies included 180 (0.7%) cases of preterm PE, 450 (1.7%) of term PE and 25 167 (97.6%) without PE. In combined first-trimester screening for preterm PE with a risk cut-off of 1 in 100, the DR was 76.7% (138/180) for preterm PE and 43.1% (194/450) for term PE, at screen-positive rate of 10.5% (2707/25 797) and FPR of 9.2% (2375/25 797). CONCLUSION: The performance of screening in the ASPRE study was comparable with that of a study of approximately 60 000 singleton pregnancies used for development of the algorithm; in that study, combined screening detected 76.6% of cases of preterm PE and 38.3% of term PE at a FPR of 10%. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Multicenter screening for pre-eclampsia by maternal factors and biomarkers at 11-13 weeks' gestation: comparison with NICE guidelines and ACOG recommendations.

OBJECTIVE: To compare the performance of screening for pre-eclampsia (PE) based on risk factors from medical history, as recommended by NICE and ACOG, with the method proposed by The Fetal Medicine Foundation (FMF), which uses Bayes' theorem to combine the a-priori risk from maternal factors, derived by a multivariable logistic model, with the results of various combinations of biophysical and biochemical measurements. METHODS: This was a prospective multicenter study of screening for PE in 8775 singleton pregnancies at 11-13 weeks' gestation. A previously published FMF algorithm was used for the calculation of patient-specific risk of PE in each individual. The detection rates (DRs) and false-positive rates (FPRs) for delivery with PE < 32, < 37 and ≥ 37 weeks were estimated and compared with those derived from application of NICE guidelines and ACOG recommendations. According to NICE, all high-risk pregnancies should be offered low-dose aspirin. According to ACOG, use of aspirin should be reserved for women with a history of PE in at least two previous pregnancies or PE requiring delivery < 34 weeks' gestation. RESULTS: In the study population, 239 (2.7%) cases developed PE, of which 17 (0.2%), 59 (0.7%) and 180 (2.1%) developed PE < 32, < 37 and ≥ 37 weeks, respectively. Screening with use of the FMF algorithm based on a combination of maternal factors, mean arterial pressure (MAP), uterine artery pulsatility index (UtA-PI) and serum placental growth factor (PlGF) detected 100% (95% CI, 80-100%) of PE < 32 weeks, 75% (95% CI, 62-85%) of PE < 37 weeks and 43% (95% CI, 35-50%) of PE ≥ 37 weeks, at a 10.0% FPR. Screening with use of NICE guidelines detected 41% (95% CI, 18-67%) of PE < 32 weeks, 39% (95% CI, 27-53%) of PE < 37 weeks and 34% (95% CI, 27-41%) of PE ≥ 37 weeks, at 10.2% FPR. Screening with use of ACOG recommendations detected 94% (95% CI, 71-100%) of PE < 32 weeks, 90% (95% CI, 79-96%) of PE < 37 weeks and 89% (95% CI, 84-94%) of PE ≥ 37 weeks, at 64.2% FPR. Screening based on the ACOG recommendations for use of aspirin detected 6% (95% CI, 1-27%) of PE < 32 weeks, 5% (95% CI, 2-14%) of PE < 37 weeks and 2% (95% CI, 0.3-5%) of PE ≥ 37 weeks, at 0.2% FPR. CONCLUSION: Performance of screening for PE at 11-13 weeks' gestation by the FMF algorithm using a combination of maternal factors, MAP, UtA-PI and PlGF, is by far superior to the methods recommended by NICE and ACOG. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Accuracy of competing-risks model in screening for pre-eclampsia by maternal factors and biomarkers at 11-13 weeks' gestation.

OBJECTIVE: To examine the diagnostic accuracy of a previously developed model for prediction of pre-eclampsia (PE) by a combination of maternal factors and biomarkers at 11-13 weeks' gestation. METHODS: This was a prospective first-trimester multicenter study of screening for PE in 8775 singleton pregnancies. A previously published algorithm was used for the calculation of patient-specific risk of PE in each individual. The detection rates (DRs) and false-positive rates (FPRs) for delivery with PE < 32, < 37 and ≥ 37 weeks were estimated and compared with those for the dataset used for development of the algorithm. RESULTS: In the study population, 239 (2.7%) cases developed PE, of which 17 (0.2%), 59 (0.7%) and 180 (2.1%) developed PE < 32, < 37 and ≥ 37 weeks, respectively. With combined screening by maternal factors, mean arterial pressure, uterine artery pulsatility index and serum placental growth factor, the DR was 100% (95% CI, 80-100%) for PE < 32 weeks, 75% (95% CI, 62-85%) for PE < 37 weeks and 43% (95% CI, 35-50%) for PE ≥ 37 weeks, at a 10% FPR. These DRs were similar to the estimated rates for the dataset used for development of the model: 89% (95% CI, 79-96%) for PE < 32 weeks, 75% (95% CI, 70-80%) for PE < 37 weeks and 47% (95% CI, 44-51%) for PE ≥ 37 weeks. CONCLUSION: Assessment of a combination of maternal factors and biomarkers at 11-13 weeks provides effective first-trimester screening for preterm PE. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Effect of pregestational diabetes mellitus on first trimester placental characteristics: three-dimensional placental volume and power Doppler indices.

OBJECTIVE: To investigate whether pregestational diabetes mellitus (DM) induces changes in vascular placental development detectable at first trimester. METHODS: This was a prospective case-control study in 69 women with pregestational DM and 94 controls undergoing first-trimester combined screening for aneuploidies. Maternal characteristics, fetal nuchal translucency thickness, maternal serum pregnancy-associated plasma protein A (PAPP-A) and free ß human chorionic gonadotrophin (ß-hCG) were evaluated. Three-dimensional ultrasound was used to measure placental volume and three dimensional power Doppler (3D-PD) placental vascular indices including: vascularization index (VI), flow index (FI) and vascularization flow index (VFI). Pregnancy-associated hypertensive complications (PAHC) and perinatal outcomes were analyzed. The total group of diabetic women and the group of diabetic women without PAHC were compared separately with the control group. RESULTS: 3D-PD placental vascular indexes were significantly lower in women with DM than in controls (VI p = 0.007, FI p = 0.003 and VFI p = 0.04). These differences remained on excluding cases with PAHC in the DM group. No differences were found in placental volumes between the DM group and controls. Serum PAPP-A levels were also lower in diabetic women (p < 0.02) and negatively correlated with the degree of maternal metabolic control at first trimester. CONCLUSIONS: Pregestational DM induces demonstrable alterations in first trimester placental development, with significantly reduced placental vascularization indices and PAPP-A values. This effect is independent of the later development of PAHC.

First-trimester screening for large-for-gestational-age infants.

OBJECTIVES: To examine the relationship between newborn birth weight and first-trimester uterine artery (UtA) pulsatility index (PI), maternal characteristics, serum pregnancy-associated plasma protein-A (PAPP-A), free ß-human chorionic gonadotropin (ß-hCG) and fetal nuchal translucency (NT) thickness. We also examined the results of screening for large-for-gestational-age (LGA) neonates by an integrated first-trimester approach incorporating these parameters. METHODS: We evaluated maternal characteristics, fetal NT, PAPP-A, free ß-hCG and UtA-PI in 2097 singleton pregnancies at 11 + 0 to 13 + 6 weeks' gestation. Linear models based on quasi Akaike's Information Criterion were used to determine the best predictive model for fetal birth weight. The patient-specific risk of delivering an LGA infant was derived from multiple logistic regression analysis and the performance of screening was determined by receiver-operating characteristics curve analysis. RESULTS: The best predictive models for fetal birth weight included UtA-PI, PAPP-A, NT, parity, maternal age, smoking status, weight, height and free ß-hCG. In pregnancies delivering LGA newborns compared with non-LGA pregnancies, PAPP-A and NT thickness were significantly increased (P = 0.016 and 0.001, respectively) and UtA-PI was significantly decreased (P = 0.011). A combination of maternal factors with PAPP-A, fetal NT and UtA-PI identified 34.4% of LGA newborns for a false-positive rate of 10%. CONCLUSIONS: This study showed an association between newborn birth weight and maternal factors, and first-trimester PAPP-A, ß-hCG, fetal NT and UtA-PI. Together, these factors can be used to identify over a third of pregnancies that will deliver LGA infants.

Acute fatty liver of pregnancy: analysis of five consecutive cases from a tertiary centre.

Acute fatty liver of pregnancy is a rare cause of jaundice and liver failure associated with high maternal and fetal mortality. We analysed five consecutive cases of acute fatty liver of pregnancy, along with the associated morbidity, mortality and complications. Between January 1999 and January 2008, a total of 68,524 deliveries were assisted at the Obstetrics and Gynaecology Department of the Hospital Universitario Materno-Infantil de Canarias (Canaries University Hospital Maternity Ward); among them, five cases of acute fatty liver of pregnancy were identified.

Influence of nuchal cord on ductus venosus assessment at 11 to 13 + 6 weeks' gestation.

OBJECTIVES: To assess the influence of the presence of nuchal cord (NC) on the evaluation of the fetal ductus venosus flow velocity waveform (DV-FVW). METHODS: This prospective study included 1174 normal non-selected singleton pregnancies between 11 and 13 + 6 weeks' gestation. We recorded the presence or absence of NC around the fetal neck, and assessed its relationship with the qualitative assessment and quantitative measurement of the DV-FVW. RESULTS: We observed NC around the fetal neck in 6.73% of cases and detected reversed flow of the a-wave of the DV-FVW in 2.98% of cases. In the group without NC, 21 of 1095 had reversed flow in the DV-FVW (1.9%; 95% CI, 1.28-3.02), whereas in the group with NC, 14 of 79 had reversed flow in the DV-FVW (17.7%; 95% CI, 16.67-40.35). We found a lower pulsatility index in fetuses without NC in comparison to those with NC (P < 0.001). We also found an association between the presence of NC and an increased occurrence of absent and reversed a-wave of the flow velocity waveforms (P < 0.001). On multivariate logistic regression analysis, a much higher occurrence of reversed DV-FVW a-wave was detected in fetuses with NC and smaller crown-rump length, and a much higher occurrence of absent DV-FVW a-wave was found in fetuses with NC and a higher maternal body mass index. CONCLUSIONS: The presence of NC modifies the sonographic findings in the qualitative and quantitative evaluation of the DV-FVW.

Contribution of the myocardial performance index and aortic isthmus blood flow index to predicting mortality in preterm growth-restricted fetuses.

OBJECTIVES: To evaluate the predictive value for perinatal death of the myocardial performance index (MPI) and aortic isthmus flow index (IFI), as isolated parameters and in a combined model including currently used Doppler indices, in preterm growth restricted (IUGR) fetuses. METHODS: Umbilical artery, fetal middle cerebral artery (MCA) and ductus venosus (DV) pulsatility indices (PIs) were recorded, along with IFI and MPI, in a cohort of 97 preterm (delivered at between 24 and 34 weeks) IUGR fetuses. Logistic regression analysis was performed to identify those variables that were independently associated with perinatal mortality, and an algorithm to estimate probability of death was constructed including the best combination of parameters. RESULTS: With the exception of MCA, all Doppler indices were significantly associated with perinatal death as isolated parameters, but only DV-PI and MPI were found to be independent predictors on multivariate analysis. An algorithm combining DV atrial flow (positive or absent/reversed) and MPI (normal or above 95(th) percentile) had a better predictive accuracy than did any single parameter. The risk for death in IUGR fetuses below 28 weeks' gestation with present atrial flow in the DV and normal MPI was 18%, with either characteristic abnormal it was 70-73%, and with both abnormal it was 97%. The risk for death in IUGR fetuses above 28 weeks with present atrial flow in the DV and normal MPI was 0.1%, with either abnormal it was 6-7%, and with both abnormal it was 45%. CONCLUSIONS: MPI is an independent predictor of perinatal death in preterm IUGR fetuses with accuracy similar to that of DV flow. A combination of DV flow with MPI may better stratify the estimated probability of death. IFI does not add to the prediction of perinatal death when used in combination with DV flow.

Hypertensive disorders in pregnancy: screening by uterine artery Doppler at 11-13 weeks.

OBJECTIVES: To examine the performance of screening for hypertensive disorders in pregnancy by a combination of the maternal factor-derived a-priori risk with the uterine artery (UtA) pulsatility index (PI) and to determine whether it is best in such screening to use the mean PI of the two arteries, the highest PI or the lowest PI. METHODS: This was a prospective screening study for pre-eclampsia (PE) requiring delivery before 34 weeks (early PE), late PE and gestational hypertension (GH) in women attending their routine first hospital visit in pregnancy at 11 + 0 to 13 + 6 weeks of gestation. Maternal history was recorded and color flow Doppler imaging was used to measure the left and right UtA-PI. The performance of screening for PE and GH by a combination of the maternal factor-derived a-priori risks determined in a previous study and the UtA-PI was assessed. RESULTS: There were 8061 (96.4%) cases unaffected by PE or GH, 37 (0.4%) that developed early PE, 128 (1.5%) with late PE and 140 (1.7%) with GH. The lowest, mean and highest UtA-PI were significantly higher in early PE and late PE than in the controls (P < 0.0001) and in early PE than late PE (P < 0.0001). The lowest UtA-PI was higher in GH than in controls (P = 0.014). The best performance in screening was provided by the lowest PI. The detection rate of early PE at a 10% false-positive rate increased from 47% in screening by maternal factors alone to 81% in screening by maternal factors and the lowest UtA-PI. The respective detection rates for late PE increased from 41% to 45% and those for GH increased from 31% to 35%. CONCLUSIONS: The patient-specific risk for PE and GH can be derived by combining the disease-specific maternal factor-derived a-priori risk with the measurement of the lowest UtA-PI in a multivariate regression model.

Three-dimensional sonographic calculation of the volume of intracranial structures in growth-restricted and appropriate-for-gestational age fetuses.

OBJECTIVES: To evaluate the feasibility and reproducibility of volume segmentation of fetal intracranial structures using three-dimensional (3D) ultrasound imaging, and to estimate differences in the volume of intracranial structures between intrauterine growth-restricted (IUGR) and appropriate-for-gestational age (AGA) fetuses. METHODS: Total intracranial, frontal, thalamic and cerebellar volumes were measured using 3D ultrasound imaging and Virtual Organ Computer-aided AnaLysis (VOCAL) in 39 IUGR and 39 AGA fetuses matched for gestational age, at 28-34 weeks of gestation. Volumes of, and ratios between, structures were estimated, and differences between IUGR and AGA fetuses were calculated. Volume measurements were performed by two observers, and interobserver and intraobserver intraclass correlation coefficients (ICCs) were calculated for each structure. RESULTS: Volumes were satisfactorily obtained in all fetuses. All net volumes except those for the thalamus (P = 0.23) were significantly smaller (P = 0.001) in IUGR fetuses. After adjusting volumes for biparietal diameter the frontal volume was significantly smaller (P = 0.02) and the thalamic volume significantly greater (P = 0.03) in IUGR fetuses than in AGA fetuses. Significant intergroup differences in the ratios between structures were found only in those involving the frontal region. Interobserver ICCs were as follows: total intracranial 0.97 (95% CI, 0.92-0.98), cerebellar 0.69 (95% CI, 0.44-0.75), frontal 0.66 (95% CI, 0.42-0.79) and thalamic 0.54 (95% CI, 0.37-0.72). CONCLUSIONS: IUGR fetuses show differences in the volume of intracranial structures compared with AGA fetuses, with the largest difference found in the frontal region. These differences might be explained by in-utero processes of neural reorganization induced by chronic hypoxia.

First-trimester maternal serum pregnancy-associated plasma protein-A and pre-eclampsia.

OBJECTIVES: To examine the relationship between low maternal serum pregnancy-associated plasma protein-A (PAPP-A) and uterine artery pulsatility index (UtA-PI) at 11+0 to 13+6 weeks with subsequent development of pre-eclampsia (PE). METHODS: UtA-PI and serum PAPP-A were measured in women attending for routine care at 11+0 to 13+6 weeks of gestation. In the population, 156 (1.9%) women developed PE, including 32 (0.4%) in whom delivery was before 34 weeks (early PE) and 124 (1.5%) with delivery at 34 weeks or more (late PE); 7895 (98.1%) women had no PE. Regression analysis was used to examine which of the factors amongst maternal characteristics, log PAPP-A multiples of the median (MoM) and log UtA-PI MoM contributed to the prediction of PE. RESULTS: The median PAPP-A MoM was 1.002 (interquartile range (IQR), 0.685-1.411) in the unaffected group, 0.555 (IQR, 0.463-0.922) in early PE and 0.911 (IQR, 0.580-1.247) in late PE. Serum PAPP-A was below the 5th centile in 21.9% of early PE and 6.5% of late PE cases. The PAPP-A-related patient-specific risk for PE was strongly influenced by maternal characteristics. There was a significant association between log UtA-PI MoM and log PAPP-A MoM (P=0.001), and the detection rate of screening for PE by maternal variables and UtA-PI was not improved by inclusion of PAPP-A. Regression analysis was used to establish tables that allow modification of the maternal history and PAPP-A-related patient-specific risk for PE by the measurement of UtA-PI. CONCLUSIONS: Low PAPP-A is a marker for subsequent development of PE. The PAPP-A-related patient-specific risk for PE can be modified by the measurement of UtA-PI.

Síndrome onfalocele-extrofia vesical-ano imperforado-defectos espinales (OEIS) / Omphalocele-bladder exstrophy-imperforate anus-spina bifida (OEIS Complex)

Se describe un caso de onfalocele-extrofia vesical-anoimperforado-defectos espinales diagnosticado en el segundo trimestre de gestación

We describe to a case of onphalocele-bladder extrophy-inperforate anus-spinal defects diagnosed in thesecond trimester of gestation

Uterine artery Doppler at 11 + 0 to 13 + 6 weeks and 21 + 0 to 24 + 6 weeks in the prediction of pre-eclampsia.

OBJECTIVE: To evaluate the performance of screening for pre-eclampsia by uterine artery pulsatility index (PI) at 11 + 0 to 13 + 6 weeks' gestation and the change in uterine artery PI between 11 + 0 to 13 + 6 and 21 + 0 to 24 + 6 weeks. METHODS: In 3107 singleton pregnancies attending for routine care at 11 + 0 to 13 + 6 and 21 + 0 to 24 + 6 weeks' gestation we recorded maternal characteristics and medical and obstetric history, and measured uterine artery PI. The distributions of uterine artery PI were made Gaussian after logarithmic transformation and the log of the ratio of uterine artery PI at 21 + 0 to 24 + 6 weeks to that at 11 + 0 to 13 + 6 weeks was calculated. Multiple regression analysis was used to determine which of the maternal variables and Doppler findings were significant predictors of early and late pre-eclampsia. The performance of screening was described by receiver-operating characteristics curves. RESULTS: Pre-eclampsia developed in 93 (3.0%) pregnancies, including 22 (0.7%) in which delivery was before 34 weeks (early pre-eclampsia) and 71 (2.3%) with delivery at 34 weeks or more (late pre-eclampsia). Seventy-three (2.3%) women developed gestational hypertension, 346 (11.1%) delivered small-for-gestational-age (SGA) babies with no hypertensive disorders and 2595 (83.5%) were unaffected by pre-eclampsia, gestational hypertension or SGA. Multiple regression analysis demonstrated that maternal variables, uterine artery PI at 11 + 0 to 13 + 6 weeks and the change in uterine artery PI between 11 + 0 to 13 + 6 and 21 + 0 to 24 + 6 weeks' gestation provided significant independent contributions to the prediction of pre-eclampsia. For a false positive rate of 5% the predicted detection rates of early and late pre-eclampsia were 90.9 and 31.0%, respectively. The same performance of screening was achieved by reserving second-trimester testing for only the 20% of women at the highest risk after first-trimester screening. CONCLUSION: The decrease in uterine artery PI between 11 + 0 to 13 + 6 and 21 + 0 to 24 + 6 weeks is steeper in pregnancies with a normal outcome than in those developing pre-eclampsia. Effective screening for pre-eclampsia can be achieved by the Doppler measurement of uterine artery PI at 11 + 0 to 13 + 6 weeks and the change in PI between 11 + 0 to 13 + 6 and 21 + 0 to 24 + 6 weeks.

Ductus venosus Doppler in fetuses with cardiac defects and increased nuchal translucency thickness.

OBJECTIVE: To examine the possible role of Doppler ultrasound assessment of ductus venosus blood flow in screening for major cardiac defects in chromosomally normal fetuses with increased nuchal translucency (NT) thickness at 11 + 0 to 13 + 6 weeks' gestation. METHODS: Ductus venosus blood flow velocity waveforms were obtained immediately before chorionic villus sampling for fetal karyotyping in fetuses with NT thickness of 3.5 mm or more at 11 + 0 to 13 + 6 weeks of gestation. In the chromosomally normal group fetal echocardiography was performed by a specialist pediatric cardiologist at 11 + 0 to 13 + 6 weeks and/or 18-22 weeks' gestation. RESULTS: Major cardiac defects were diagnosed in 16 (8.4%) of the 191 chromosomally normal fetuses. Reversed or absent flow in the ductus venosus during atrial contraction was observed in 11 of the 16 (68.8%) fetuses with cardiac defects and in 40 of the 175 (22.9%) with no cardiac defects. Multivariate analysis demonstrated that the prevalence of an abnormal A-wave in the ductus venosus in fetuses without major cardiac defects increased with fetal NT thickness (odds ratio (OR), 1.463; 95% CI, 1.183-1.809; P < 0.0001) but in those with cardiac defects it did not change significantly with NT thickness (OR, 2.054; 95% CI, 0.573-7.360; P = 0.269). The likelihood ratio for a major cardiac defect when the ductus venosus flow was abnormal decreased with fetal NT thickness from 4.58 at NT 3.5 mm to 2.47 for NT 5.5 mm, and the likelihood ratio when the ductus venosus flow was normal increased from 0.37 at NT 3.5 mm to 0.43 for NT 5.5 mm. CONCLUSION: In chromosomally normal fetuses with increased NT the finding of an absent or reversed A-wave in the ductus venosus is associated with a three-fold increase in the likelihood of a major cardiac defect, whereas the finding of normal ductal flow is associated with a halving in risk for such defects.

Choroid plexus cyst, intracardiac echogenic focus, hyperechogenic bowel and hydronephrosis in screening for trisomy 21 at 11 + 0 to 13 + 6 weeks.

OBJECTIVES: To investigate the potential value of choroid plexus cyst, intracardiac echogenic focus, hydronephrosis and hyperechogenic bowel as markers of trisomy 21 at 11 + 0 to 13 + 6 weeks. METHODS: We examined three-dimensional volumes from 228 fetuses with trisomy 21 and 797 chromosomally normal fetuses at 11 + 0 to 13 + 6 weeks of gestation. We looked for choroid plexus cysts with a minimum diameter of 1.5 mm, intracardiac echogenic focus, hydronephrosis with a minimum anteroposterior diameter of the pelvis of 1.5 mm and hyperechogenic bowel. RESULTS: The prevalence of intracardiac echogenic focus, hydronephrosis and hyperechogenic bowel was significantly higher in trisomy 21 than in normal fetuses (9.6% vs. 1.5%, 17.1% vs. 5.3% and 11.4% vs. 2.4%, respectively). There was no significant difference between the two groups in the prevalence of choroid plexus cysts (7.5% vs. 5.0%). There were no significant differences in crown-rump length or nuchal translucency thickness in either chromosomally normal or trisomy 21 fetuses between those with and those without any one of the markers. CONCLUSIONS: At 11 + 0 to 13 + 6 weeks the prevalence of intracardiac echogenic focus, hydronephrosis and hyperechogenic bowel is higher in trisomy 21 than in chromosomally normal fetuses. As there is no significant association between the presence of these markers and nuchal translucency thickness, they could be included in the assessment of risk to improve accuracy of screening.