First trimester risk of preeclampsia and rate of spontaneous birth in patients without preeclampsia.

BACKGROUND: First-trimester screening for preeclampsia using a combination of maternal risk factors and mean arterial pressure, uterine artery pulsatility index, and placental growth factor, as proposed by the Fetal Medicine Foundation, provides effective prediction of preterm preeclampsia. Placental dysfunction is a potential precursor of spontaneous birth. OBJECTIVE: The objective of this study was to examine if the estimated risk of preeclampsia is associated with the gestational age at onset of spontaneous delivery in the absence of preeclampsia. STUDY DESIGN: This was a secondary analysis of the data from the Screening programme for pre-eclampsia trial in which there was a comparison of the performance of first-trimester screening for preterm preeclampsia using the Fetal Medicine Foundation model vs a traditional history-based risk scoring system. A subgroup of women from the trial with spontaneous onset of delivery (labor with intact membranes or preterm prelabor rupture of membranes) was included in this study and was arbitrarily divided into 3 groups according to the risk for preterm preeclampsia as determined by the Fetal Medicine Foundation model at 11 to 13 weeks' gestation as follows: group 1 low risk (˂1/100); group 2 intermediate risk (1/50 to 1/100); and group 3 high risk (˃1/50). A survival analysis was carried out using a Kaplan-Meier estimator and a Cox regression analysis with stratification by the 3 preeclampsia risk groups. Occurrence of spontaneous birth in the study groups was compared using log-rank tests and hazard ratios. RESULTS: The study population comprised 10,820 cases with delivery after spontaneous onset of labor among the 16,451 cases who participated in the Screening programme for pre-eclampsia trial. There were 9795 cases in group 1, 583 in group 2, and 442 in group 3. The gestational age at delivery was <28, <32, <35, <37, and <40 weeks in 0.29%, 0.64%, 1.68%, 4.52%, and 44.97% of cases, respectively, in group 1; 0.69%, 1.71%, 3.26%, 7.72%, and 55.23% of cases, respectively, in group 2; and 0.45%, 1.81%, 5.66%, 13.80%, and 63.12% of cases, respectively, in group 3. The curve profile of gestational age at spontaneous birth in the 3 study groups was significantly different overall and in pairwise comparisons (P values <.001). The Cox regression analysis showed that risks increased for spontaneous birth by 18% when the intermediate-risk group was compared with the low-risk group (P˂.001) and by 41% when the high-risk group was compared with the low-risk group (P˂.001). CONCLUSION: In this study that investigated birth after spontaneous onset of labor in women without preeclampsia, there were 2 major findings. First, the duration of pregnancy decreased with increasing first-trimester risk for preeclampsia. Second, in the high-risk group, when compared with the low-risk group, the risk for spontaneous birth was 4 times higher at a gestational age of 24 to 26 weeks, 3 times higher at 28 to 32 weeks, and 2 times higher at 34 to 39 weeks. These differences present major clinical implications for antepartum counselling, monitoring, and interventions in these pregnancies.

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

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

Atypicality index as an add-on to combined first-trimester screening for chromosomal aberrations.

OBJECTIVES: To compute a set of atypicality indices based on combined first-trimester screening (cFTS) markers and second-trimester estimated fetal weight (EFW), and to demonstrate their potential in identifying pregnancies at reduced or increased risk of chromosomal aberrations following a low-risk cFTS result. METHODS: The atypicality index quantifies the unusualness of an individual set of measurements relative to a reference distribution and can be computed from any variables or measurements available. A score of 0% on the atypicality index represents the most typical profiles, while a score of 100% indicates the highest level of atypicality. From the Danish Fetal Medicine Database, we retrieved data on all pregnant women seen for cFTS in the Central Denmark Region between January 2008 and December 2018. All pregnancies with a cytogenetic or molecular analysis obtained prenatally, postnatally or following pregnancy loss or termination were identified. A first-trimester atypicality index (AcFTS) was computed based on nuchal translucency (NT) thickness, maternal serum free ß-human chorionic gonadotropin (ß-hCG) and pregnancy-associated plasma protein-A (PAPP-A). Furthermore, a second-trimester index (AcFTS + EFW) was computed from cFTS markers and EFW from a routine second-trimester anomaly scan. All pregnancies were stratified into subgroups based on their atypicality levels and their cFTS risk estimates. The risk of chromosomal aberrations in each subgroup was then compared with the overall prevalence, and a graphical presentation of the multivariate measurement profiles was developed. RESULTS: We retrieved data on 145 955 singleton pregnancies, of which 9824 (6.7%) were genetically examined. Overall, 1 in 122 (0.82% (95% CI, 0.77-0.87%)) of all pregnancies seen for cFTS were affected by a fetal chromosomal aberration, and in screen-negative pregnancies (cFTS trisomy 21 risk < 1 in 100 and/or trisomy 18/13 risk < 1 in 50), 0.41% (95% CI, 0.38-0.44%) were affected. In screen-negative pregnancies with a typical first-trimester profile (AcFTS < 80%), the risk of chromosomal aberrations was significantly reduced (0.28%) compared with the overall risk. The risk of chromosomal aberrations increased with higher atypicality index to 0.49% (AcFTS [80-90%)), 1.52% (AcFTS [90-99%)) and 4.44% (AcFTS ≥ 99%) and was significantly increased in the two most atypical subgroups. The same applied for the second-trimester atypicality index, with risks of chromosomal aberrations of 0.76% and 4.16% in the two most atypical subgroups (AcFTS + EFW [90-99%) and AcFTS + EFW ≥ 99%, respectively). CONCLUSIONS: As an add-on to cFTS, the atypicality index identifies women with typical measurement profiles, which may provide reassurance, whereas atypical profiles may warrant specialist referral and further investigation. In pregnancies identified as low risk on cFTS but with a highly atypical distribution of NT, PAPP-A and ß-hCG, the risk of a chromosomal aberration is substantially increased. The atypicality index optimizes the interpretation of pre-existing prenatal screening profiles and is not limited to cFTS markers or EFW. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

Evaluation of screening performance of first-trimester competing-risks prediction model for small-for-gestational age in Asian population.

OBJECTIVE: To examine the external validity of the Fetal Medicine Foundation (FMF) competing-risks model for the prediction of small-for-gestational age (SGA) at 11-14 weeks' gestation in an Asian population. METHODS: This was a secondary analysis of a multicenter prospective cohort study in 10 120 women with a singleton pregnancy undergoing routine assessment at 11-14 weeks' gestation. We applied the FMF competing-risks model for the first-trimester prediction of SGA, combining maternal characteristics and medical history with measurements of mean arterial pressure (MAP), uterine artery pulsatility index (UtA-PI) and serum placental growth factor (PlGF) concentration. We calculated risks for different cut-offs of birth-weight percentile (< 10th , < 5th or < 3rd percentile) and gestational age at delivery (< 37 weeks (preterm SGA) or SGA at any gestational age). Predictive performance was examined in terms of discrimination and calibration. RESULTS: The predictive performance of the competing-risks model for SGA was similar to that reported in the original FMF study. Specifically, the combination of maternal factors with MAP, UtA-PI and PlGF yielded the best performance for the prediction of preterm SGA with birth weight < 10th percentile (SGA < 10th ) and preterm SGA with birth weight < 5th percentile (SGA < 5th ), with areas under the receiver-operating-characteristics curve (AUCs) of 0.765 (95% CI, 0.720-0.809) and 0.789 (95% CI, 0.736-0.841), respectively. Combining maternal factors with MAP and PlGF yielded the best model for predicting preterm SGA with birth weight < 3rd percentile (SGA < 3rd ) (AUC, 0.797 (95% CI, 0.744-0.850)). After excluding cases with pre-eclampsia, the combination of maternal factors with MAP, UtA-PI and PlGF yielded the best performance for the prediction of preterm SGA < 10th and preterm SGA < 5th , with AUCs of 0.743 (95% CI, 0.691-0.795) and 0.762 (95% CI, 0.700-0.824), respectively. However, the best model for predicting preterm SGA < 3rd without pre-eclampsia was the combination of maternal factors and PlGF (AUC, 0.786 (95% CI, 0.723-0.849)). The FMF competing-risks model including maternal factors, MAP, UtA-PI and PlGF achieved detection rates of 42.2%, 47.3% and 48.1%, at a fixed false-positive rate of 10%, for the prediction of preterm SGA < 10th , preterm SGA < 5th and preterm SGA < 3rd , respectively. The calibration of the model was satisfactory. CONCLUSION: The screening performance of the FMF first-trimester competing-risks model for SGA in a large, independent cohort of Asian women is comparable with that reported in the original FMF study in a mixed European population. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Management and outcome of fetal abdominal cysts in first trimester: systematic review of the literature.

OBJECTIVES: The finding of an abdominal cyst during pregnancy has an estimated prevalence of 1 in 1000 pregnancies, mostly in second and third trimester. The detection of a fetal abdominal cyst during the first trimester scan is a rare event, whose natural history and prognosis are often unknown and unpredictable as these anomalies can be related to various underlying conditions and originate from different structures. The aim of this study is to evaluate the outcome of fetal abdominal cysts detected in the first trimester in order to understand their possible clinical significance and to offer the proper management according to the available data. METHODS: We present a case report of a first trimester fetal abdominal cyst detected with subsequent diagnosis of congenital multiple arthrogryposis and we performed a systematic review of the literature to identify the incidence and the outcomes of similar cases. The systematic literature review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement 25 and registered with PROSPERO (CRD42023491729). RESULTS: A total of 60 cases of first trimester abdominal cysts were included. Of these, 35% were associated with concurrent or late onset structural anomalies, as in our case report, and 65% were isolated. In pregnancies with isolated fetal abdominal cysts, 56% had a completely normal outcome. CONCLUSIONS: The finding of an abdominal cyst during the first trimester of pregnancy is in most cases an isolated event with a moderate to good prognosis but it could also be an early sign of other associated abnormalities, including arthrogryposis. Increased ultrasound surveillance and additional genetic testing to rule out possible associated anomalies are pivotal to assess the risk of adverse pregnancy outcomes and to provide appropriate counselling to the patient. This article is protected by copyright. All rights reserved.

Development of a 3D-printed nuchal translucency model: a pilot study for prenatal ultrasound training.

BACKGROUND: We used two 3D ultrasound volumes of fetal heads at 13 weeks to create live-size 3D-printed phantoms with a view to training or assessment of diagnostic abilities for normal and abnormal nuchal translucency measurements. The phantoms are suitable for use in a water bath, imitating a real-life exam. They were then used to study measurement accuracy and reproducibility in examiners of different skill levels. METHODS: Ultrasound scans of a 13 + 0-week fetus were processed using 3D Slicer software, producing a stereolithography file for 3D printing. The model, crafted in Autodesk Fusion360™, adhered to FMF guidelines for NT dimensions (NT 2.3 mm). Additionally, a model with pathologic NT was designed (NT 4.2 mm). Printing was performed via Formlabs Form 3® printer using High Temp Resin V2. The externally identical looking 3D models were embedded in water-filled condoms for ultrasound examination. Eight specialists of varying expertise levels conducted five NT measurements for each model, classifying them in physiological and abnormal models. RESULTS: Classification of the models in physiological or abnormal NT resulted in a detection rate of 100%. Average measurements for the normal NT model and the increased NT model were 2.27 mm (SD ± 0.38) and 4.165 mm (SD ± 0.51), respectively. The interrater reliability was calculated via the intraclass correlation coefficient (ICC) which yielded a result of 0.883, indicating robust agreement between the raters. Cost-effectiveness analysis demonstrated the economical nature of the 3D printing process. DISCUSSION: This study underscores the potential of 3D printed fetal models for enhancing ultrasound training through high inter-rater reliability, consistency across different expert levels, and cost-effectiveness. Limitations, including population variability and direct translation to clinical outcomes, warrant further exploration. The study contributes to ongoing discussions on integrating innovative technologies into medical education, offering a practical and economical method to acquire, refine and revise diagnostic skills in prenatal ultrasound. Future research should explore broader applications and long-term economic implications, paving the way for transformative advancements in medical training and practice.

First-trimester serum biomarkers in twin pregnancies and adverse obstetric outcomes-a single center cohort study.

PURPOSE: This study aimed to determine the association of first-trimester maternal serum biomarkers with preterm birth (PTB), fetal growth restriction (FGR) and hypertensive disorders of pregnancy (HDP) in twin pregnancies. METHODS: This is a retrospective cohort study of twin pregnancies followed at Maternidade Dr. Alfredo da Costa, Lisbon, Portugal, between January 2010 and December 2022. We included women who completed first-trimester screening in our unit and had ongoing pregnancies with two live fetuses, and delivered after 24 weeks. Maternal characteristics, pregnancy-associated plasma protein-A (PAPP-A) and ß-human chorionic gonadotropin (ß-hCG) levels were analyzed for different outcomes: small for gestational age (SGA), gestational hypertension (GH), early and late-onset pre-eclampsia (PE), as well as the composite outcome of PTB associated with FGR and/or HDP. Univariable, multivariable logistic regression analyses and receiver-operating characteristic curve were used. RESULTS: 466 twin pregnancies met the inclusion criteria. Overall, 185 (39.7%) pregnancies were affected by SGA < 5th percentile and/or HDP. PAPP-A demonstrated a linear association with gestational age at birth and mean birth weight. PAPP-A proved to be an independent risk factor for SGA and PTB (< 34 and < 36 weeks) related to FGR and/or HDP. None of the women with PAPP-A MoM > 90th percentile developed early-onset PE or PTB < 34 weeks. CONCLUSION: A high serum PAPP-A (> 90th percentile) ruled out early-onset PE and PTB < 34 weeks. Unless other major risk factors for hypertensive disorders are present, these women should not be considered candidates for aspirin prophylaxis. Nevertheless, close monitoring of all TwP for adverse obstetric outcomes is still recommended.

Diagnostic Role of Cell-Free miRNAs in Identifying Placenta Accreta Spectrum during First-Trimester Screening.

Placenta accreta spectrum (PAS) is a severe complication of pregnancy associated with excessive invasion of cytotrophoblast cells at the sites of the endometrial-myometrial interface and the myometrium itself in cases of adherent (creta) and invasive (increta and percreta) forms, respectively. This leads to a high risk of massive blood loss, maternal hysterectomy, and preterm birth. Despite advancements in ultrasound protocols and found associations of alpha-fetoprotein, PAPP-A, hCG, PLGF, sFlt-1, IL-8, and IL-33 peripheral blood levels with PAS, there is a high need for an additional non-invasive test to improve the diagnostic accuracy and to select the real PAS from the suspected ones in the first-trimester screening. miRNA signatures of placental tissue, myometrium, and blood plasma from women with PAS in the third trimester of pregnancy, as well as miRNA profiles in exosomes from the blood serum of women in the first trimester with physiologically progressing pregnancy, complicated by PAS or pre-eclampsia, were obtained using deep sequencing. Two logistic regression models were constructed, both featuring statistically significant parameters related to the levels of miR-26a-5p, miR-17-5p, and miR-101-3p, quantified by real-time PCR in native blood serum. These models demonstrated 100% sensitivity in detecting PAS during the first pregnancy screening. These miRNAs were identified as specific markers for PAS, showing significant differences in their blood serum levels during the first trimester in the PAS group compared to those in physiological pregnancies, early- or late-onset pre-eclampsia groups. Furthermore, these miRNAs exhibited differential expression in the PAS placenta and/or myometrium in the third trimester and, according to data from the literature, control angiogenesis. Significant correlations were found between extracellular hsa-miR-101-3p and nuchal translucency thickness, hsa-miR-17-5p and uterine artery pulsatility index, and hsa-miR-26a-5p and hsa-miR-17-5p with PLGF. The developed test system for early non-invasive PAS diagnosis based on the blood serum level of extracellular miR-26a-5p, miR-17-5p, and miR-101-3p can serve as an auxiliary method for first-trimester screening of pregnant women, subject to validation with independent test samples.

Impact of COVID-19 and vaccination on first and second trimester screening results.

COVID-19 has been shown to affect pregnant women. Since pregnant women are at risk of this infection, vaccination against COVID-19 has been suggested as an imperative way to diminish rate of COVID-19 in this population. In the current observational study, we have collected data of first and second trimester screening (FTS and STS) from pregnant women who were infected with SARS-CoV-2 and/or vaccinated against COVID-19 during their pregnancy, and compared this data with a group of control pregnant women. The cohort included 4612 and 2426 women referred for FTS and STS, respectively. There was no significant difference in median values of Pregnancy-associated plasma protein A (PAPP-A) and human chorionic gonadotropin-beta subunit (ßHCG) between infected women and controls. Moreover, these levels were not different between "Infected + vaccinated" and "Only vaccinated" groups. However, median values of PAPP-A and ßHCG were higher in "Infected + vaccinated" and "Only vaccinated" groups compared with "Infected" and "Control" groups (P < 0.001). Median values of unconjugated Estriol (uE3) and ßHCG markers were not different between "Only vaccinated" and "Control" groups, yet both markers were elevated in "Infected" and "Infected + vaccinated" groups compared with other groups. AFP values were higher in "Infected" group (P = 0.012). However, multiple of the median (MoM) and risk of open spina bifida (OSB) were not affected. Finally, median of calculated risk of trisomy 18 was lower in "Infected" and "Vaccinated" groups compared with controls (P = 0.007). Moreover, AstraZeneca and Sinopharm vaccines were associated with elevation of the calculated risk values of trisomy 21 and trisomy 18 (P < 0.001). While Sinopharm did not affect nuchal translucency (NT) and NT MoM (P = 0.13), AstraZeneca and Barakat increased and decreased these values, respectively (P values = 0.0027 and 0.015, respectively). Taken together, COVID-19 during pregnancy might be associated with some adverse obstetric outcomes. Besides, vaccination against this infection might affect the results of STS or FTS.

First-trimester preterm preeclampsia prediction with metabolite biomarkers: differential prediction according to maternal body mass index.

BACKGROUND: Prediction of preeclampsia risk is key to informing effective maternal care. Current screening for preeclampsia at 11 to 13 weeks of gestation using maternal demographic characteristics and medical history with measurements of mean arterial pressure, uterine artery pulsatility index, and serum placental growth factor can identify approximately 75% of women who develop preterm preeclampsia with delivery at <37 weeks of gestation. Further improvements to preeclampsia screening tests will likely require integrating additional biomarkers. Recent research suggests the existence of distinct maternal risk profiles. Therefore, biomarker evaluation should account for the possibility that a biomarker only predicts preeclampsia in a specific maternal phenotype. OBJECTIVE: This study aimed to verify metabolite biomarkers as preterm preeclampsia predictors early in pregnancy in all women and across body mass index groups. STUDY DESIGN: Observational case-control study drawn from a large prospective study on the early prediction of pregnancy complications in women attending their routine first hospital visit at King's College Hospital, London, United Kingdom, in 2010 to 2015. Pregnant women underwent a complete first-trimester assessment, including the collection of blood samples for biobanking. In 11- to 13-week plasma samples of 2501 singleton pregnancies, the levels of preselected metabolites implicated in the prediction of pregnancy complications were analyzed using a targeted liquid chromatography-mass spectrometry method, yielding high-quality quantification data on 50 metabolites. The ratios of amino acid levels involved in arginine biosynthesis and nitric oxide synthase pathways were added to the list of biomarkers. Placental growth factor and pregnancy-associated plasma protein A were also available for all study subjects, serving as comparator risk predictors. Data on 1635 control and 106 pregnancies complicated by preterm preeclampsia were considered for this analysis, normalized using multiples of medians. Prediction analyses were performed across the following patient strata: all subjects and the body mass index classes of <25, 25 to <30, and ≥30 kg/m2. Adjusted median levels were compared between cases and controls and between each body mass index class group. Odds ratios and 95% confidence intervals were calculated at the mean ±1 standard deviation to gauge clinical prediction merits. RESULTS: The levels of 13 metabolites were associated with preterm preeclampsia in the entire study population (P<.05) with particularly significant (P<.01) associations found for 6 of them, namely, 2-hydroxy-(2/3)-methylbutyric acid, 25-hydroxyvitamin D3, 2-hydroxybutyric acid, alanine, dodecanoylcarnitine, and 1-(1Z-octadecenyl)-2-oleoyl-sn-glycero-3-phosphocholine. Fold changes in 7 amino acid ratios, all involving glutamine or ornithine, were also significantly different between cases and controls (P<.01). The predictive performance of some metabolites and ratios differed according to body mass index classification; for example, ornithine (P<.001) and several ornithine-related ratios (P<.0001 to P<.01) were only strongly associated with preterm preeclampsia in the body mass index of <25 kg/m2 group, whereas dodecanoylcarnitine and 3 glutamine ratios were particularly predictive in the body mass index of ≥30 kg/m2 group (P<.01). CONCLUSION: Single metabolites and ratios of amino acids related to arginine bioavailability and nitric oxide synthase pathways were associated with preterm preeclampsia risk at 11 to 13 weeks of gestation. Differential prediction was observed according to body mass index classes, supporting the existence of distinct maternal risk profiles. Future studies in preeclampsia prediction should account for the possibility of different maternal risk profiles to improve etiologic and prognostic understanding and, ultimately, clinical utility of screening tests.

Complication rate after termination of pregnancy for fetal defects.

OBJECTIVES: To assess the risk of complications in women undergoing termination of pregnancy (TOP) for fetal defects and to examine the impact of gestational age on the complication rate. METHODS: This was a retrospective study of women with a singleton pregnancy undergoing TOP at the University Hospital of Tübingen, Germany, between 2018 and 2021. TOP was performed by experienced operators according to the national protocol; dilatation and curettage (D&C) or evacuation (D&E) was used in the first and early second trimesters and induction was used later in pregnancy. The following were considered to be significant procedure-related complications: blood loss of more than 500 mL, uterine perforation, need for blood transfusion, allergic reaction, creation of a false passage (via falsa), systemic infection, readmission to hospital, any unplanned surgical procedure, such as repeat D&C/D&E or hysterectomy, and maternal death. RESULTS: The search of the hospital database identified 416 pregnancies that met the study criteria. Median maternal and gestational age at termination were 34.1 years and 17.4 weeks, respectively. In the first, second and third trimesters, respectively, 84 (20.2%), 278 (66.8%) and 54 (13.0%) pregnancies were terminated, for which D&C or D&E was used in 80 (95.2%), 21 (7.6%) and 0 (0.0%) cases. Seventy-seven (18.5%) women had at least one previous Cesarean section and 169 (40.6%) had at least one previous spontaneous delivery. Overall, 95 (22.8%) women had complications during or after TOP. A significantly higher complication rate was noted for terminations performed later in pregnancy. The median gestational age at termination was 16.6 weeks in women who did not experience complications and 20.7 weeks in those with complications (P < 0.001). The respective complication rates in the first, second and third trimesters were 6.0%, 27.0% and 27.8%. CONCLUSION: In women undergoing TOP for fetal defects, the risk of complications increases with advancing gestational age. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Atypicality index: avoiding false reassurance in prenatal screening.

OBJECTIVE: To demonstrate the application of the atypicality index as an adjunct to first-trimester risk assessment for major trisomies by the combined test. METHODS: This was a study of 123 998 Danish women with a singleton pregnancy who underwent routine first-trimester screening, including risk assessment for major trisomies. An atypicality index, which is a measure of the degree to which a profile is atypical, was produced for measurements of fetal nuchal translucency thickness and maternal serum free ß-human chorionic gonadotropin and pregnancy-associated plasma protein-A. The incidence of adverse pregnancy outcome, including miscarriage, intrauterine death and termination of pregnancy, was tabulated according to the screening result and atypicality index. RESULTS: In pregnancies with low risk and those with high risk for major trisomies according to the combined screening test, the incidence of adverse pregnancy outcome increased with increasing atypicality index. In pregnancies with a low risk for trisomies and atypicality index of ≥ 99%, the incidence of adverse outcome was 5.1 (95% CI, 3.4-7.6) times higher compared with that in low-risk pregnancies with a typical measurement profile, reflected by an atypicality index of < 80%. Similarly, in high-risk pregnancies, the incidence of adverse outcome was 7.9 (95% CI, 4.4-14.5) times higher in those with an atypicality index of ≥ 99% compared to those with an atypicality index of < 80%. Using individual profile plots, we were able to demonstrate a transparent and intuitive method for visualization of multiple variables, which can help interpret the individual combination of measurements and level of atypicality. CONCLUSIONS: In pregnancies undergoing first-trimester combined screening and classified as being at low risk for major trisomies, profiles that are typical of pregnancies with normal outcome provide additional reassurance, whereas those with an atypical profile may warrant further investigation. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.

Screening for pre-eclampsia by maternal serum glycosylated fibronectin at 11-13 weeks' gestation.

OBJECTIVE: To examine the performance of screening for preterm and term pre-eclampsia (PE) at 11-13 weeks' gestation by maternal factors and combinations of maternal serum glycosylated fibronectin (GlyFn), mean arterial pressure (MAP), uterine artery pulsatility index (UtA-PI) and serum placental growth factor (PlGF). METHODS: This was a case-control study in which maternal serum GlyFn was measured using a point-of-care device in stored samples from a non-intervention screening study of singleton pregnancies at 11 + 0 to 13 + 6 weeks' gestation. In the same samples, PlGF was measured by time-resolved fluorometry. We used samples from women who delivered with PE at < 37 weeks' gestation (n = 100), PE at ≥ 37 weeks (n = 100), gestational hypertension (GH) at < 37 weeks (n = 100), GH at ≥ 37 weeks (n = 100) and 1000 normotensive controls with no pregnancy complications. In all cases, MAP and UtA-PI had been measured during the routine 11-13-week visit. Levels of GlyFn were transformed to multiples of the expected median (MoM) values after adjusting for maternal demographic characteristics and elements of medical history. Similarly, the measured values of MAP, UtA-PI and PlGF were converted to MoMs. The competing-risks model was used to combine the prior distribution of gestational age at delivery with PE, obtained from maternal characteristics, with various combinations of biomarker MoM values to derive the patient-specific risks of delivery with PE or GH at < 37 and ≥ 37 weeks' gestation. Screening performance was estimated by examining the area under the receiver-operating-characteristics curve (AUC) and detection rate (DR) at 10% fixed false-positive rate (FPR). RESULTS: The maternal characteristics and elements of medical history with a significant effect on the measurement of GlyFn were maternal age, weight, height, race, smoking status and history of PE. In pregnancies that developed PE, GlyFn MoM was increased and the deviation from normal decreased with increasing gestational age at delivery. The DR and AUC of screening for delivery with PE at < 37 weeks' gestation by maternal factors alone were 50% and 0.834, respectively, and these increased to 80% and 0.949, respectively, when maternal risk factors were combined with MAP, UtA-PI and PlGF (triple test). The performance of the triple test was similar to that of screening by a combination of maternal factors, MAP, UtA-PI and GlyFn (DR, 79%; AUC, 0.946) and that of screening by a combination of maternal factors, MAP, PlGF and GlyFn (DR, 81%; AUC, 0.932). The performance of screening for delivery with PE at ≥ 37 weeks' gestation was poor; the DR for screening by maternal factors alone was 35% and increased to only 39% with use of the triple test. Similar results were obtained when GlyFn replaced PlGF or UtA-PI in the triple test. The DR of screening for GH with delivery at < 37 and ≥ 37 weeks' gestation by maternal factors alone was 34% and 25%, respectively, and increased to 54% and 31%, respectively, with use of the triple test. Similar results were obtained when GlyFn replaced PlGF or UtA-PI in the triple test. CONCLUSIONS: GlyFn is a potentially useful biomarker in first-trimester screening for preterm PE, but the findings of this case-control study need to be validated by prospective screening studies. The performance of screening for term PE or GH at 11 + 0 to 13 + 6 weeks' gestation by any combination of biomarkers is poor. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

Performance of first-trimester combined screening for preterm pre-eclampsia: findings from cohort of 10 110 pregnancies in Spain.

OBJECTIVE: To evaluate the diagnostic accuracy of the Fetal Medicine Foundation (FMF) competing-risks model, incorporating maternal characteristics, mean arterial pressure (MAP), uterine artery pulsatility index (UtA-PI) and placental growth factor (PlGF) (the 'triple test'), for the prediction at 11-13 weeks' gestation of preterm pre-eclampsia (PE) in a Spanish population. METHODS: This was a prospective cohort study performed in eight fetal medicine units in five different regions of Spain between September 2017 and December 2019. All pregnant women with a singleton pregnancy and a non-malformed live fetus attending a routine ultrasound examination at 11 + 0 to 13 + 6 weeks' gestation were invited to participate. Maternal demographic characteristics and medical history were recorded and MAP, UtA-PI, serum PlGF and pregnancy-associated plasma protein-A (PAPP-A) were measured following standardized protocols. Treatment with aspirin during pregnancy was also recorded. Raw values of biomarkers were converted into multiples of the median (MoM), and audits were performed periodically to provide regular feedback to operators and laboratories. Patient-specific risks for term and preterm PE were calculated according to the FMF competing-risks model, blinded to pregnancy outcome. The performance of screening for PE, taking into account aspirin use, was assessed by calculating the area under the receiver-operating-characteristics curve (AUC) and detection rate (DR) at a 10% fixed screen-positive rate (SPR). Risk calibration of the model was assessed. RESULTS: The study population comprised 10 110 singleton pregnancies, including 72 (0.7%) that developed preterm PE. In the preterm PE group, compared to those without PE, median MAP MoM and UtA-PI MoM were significantly higher, and median serum PlGF MoM and PAPP-A MoM were significantly lower. In women with PE, the deviation from normal in all biomarkers was inversely related to gestational age at delivery. Screening for preterm PE by a combination of maternal characteristics and medical history with MAP, UtA-PI and PlGF had a DR, at 10% SPR, of 72.7% (95% CI, 62.9-82.6%). An alternative strategy of replacing PlGF with PAPP-A in the triple test was associated with poorer screening performance for preterm PE, giving a DR of 66.5% (95% CI, 55.8-77.2%). The calibration plot showed good agreement between predicted risk and observed incidence of preterm PE, with a slope of 0.983 (95% CI, 0.846-1.120) and an intercept of 0.154 (95% CI, -0.091 to 0.397). CONCLUSIONS: The FMF model is effective in predicting preterm PE in the Spanish population at 11-13 weeks' gestation. This method of screening is feasible to implement in routine clinical practice, but it should be accompanied by a robust audit and monitoring system, in order to maintain high-quality screening. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

Glycosylated fibronectin improves first-trimester prediction of pre-eclampsia.

OBJECTIVE: To determine whether maternal serum glycosylated fibronectin (GlyFn) level in the first trimester increases the sensitivity of the Fetal Medicine Foundation (FMF) triple test, which incorporates mean arterial pressure, uterine artery pulsatility index and placental growth factor, when screening for pre-eclampsia (PE) in an Asian population. METHODS: This was a nested case-control study of Chinese women with a singleton pregnancy who were screened for PE at 11-13 weeks' gestation as part of a non-intervention study between December 2016 and June 2018. GlyFn levels were measured retrospectively in archived serum from 1685 pregnancies, including 101 with PE, using an enzyme-linked immunosorbent assay (ELISA), and from 448 pregnancies, including 101 with PE, using a point-of-care (POC) device. Concordance between ELISA and POC tests was assessed using Lin's correlation coefficient and Passing-Bablok and Bland-Altman analyses. GlyFn was transformed into multiples of the median (MoM) to adjust for maternal and pregnancy characteristics. GlyFn MoM was compared between PE and non-PE pregnancies, and the association between GlyFn MoM and gestational age at delivery with PE was assessed. Risk for developing PE was estimated using the FMF competing-risks model. Screening performance for preterm and any-onset PE using different biomarker combinations was quantified by area under the receiver-operating-characteristics curve (AUC) and detection rate (DR) at a 10% fixed false-positive rate (FPR). Differences in AUC between biomarker combinations were compared using the DeLong test. RESULTS: The concordance correlation coefficient between ELISA and POC measurements was 0.86 (95% CI, 0.83-0.88). Passing-Bablok analysis indicated proportional bias (slope, 1.08 (95% CI, 1.04-1.14)), with POC GlyFn being significantly higher compared with ELISA GlyFn. ELISA GlyFn in non-PE pregnancies was independent of gestational age at screening (P = 0.11), but significantly dependent on maternal age (P < 0.003), weight (P < 0.0002), height (P = 0.001), parity (P < 0.02) and smoking status (P = 0.002). Compared with non-PE pregnancies, median GlyFn MoM using ELISA and POC testing was elevated significantly in those with preterm PE (1.23 vs 1.00; P < 0.0001 and 1.18 vs 1.00; P < 0.0001, respectively) and those with term PE (1.26 vs 1.00; P < 0.0001 and 1.22 vs 1.00; P < 0.0001, respectively). GlyFn MoM was not correlated with gestational age at delivery with PE (P = 0.989). Adding GlyFn to the FMF triple test for preterm PE increased significantly the AUC from 0.859 to 0.896 (P = 0.012) and increased the DR at 10% FPR from 64.9% (95% CI, 48.7-81.1%) to 82.9% (95% CI, 66.4-93.4%). The corresponding DRs at 10% FPR for any-onset PE were 52.5% (95% CI, 42.3-62.5%) and 65.4% (95% CI, 55.2-74.5%), respectively. CONCLUSIONS: Adding GlyFn to the FMF triple test increased the screening sensitivity for both preterm and any-onset PE in an Asian population. Prospective non-intervention studies are needed to confirm these initial findings. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

A new contingent screening strategy increased detection rate of trisomy 21 in the first trimester.

BACKGROUND: Although the traditional contingent screening strategy is effective, there are still undetected low-risk trisomy 21. This study aims to define appropriate cut-off values of serum biochemical markers at low-risk and develop a strategy for sequential prenatal testing associated with first-trimester screening to increase the detection rate of trisomy 21. METHODS: This was a 9-year retrospective analysis of singleton pregnant women who underwent serum biochemical screening or combined first-trimester screening (CFTS) in the first trimester. For the low-risk group, the cut-off values of the serum biochemical markers were adjusted to determine the appropriate detection efficiency. Gravidas with abnormal serum biochemical markers at low-risk were advised to undergo further non-invasive prenatal screening (NIPS), whereas others continued with routine prenatal care. RESULTS: When cut-off values of free beta subunit of human chorionic gonadotropin (free ß-hCG) multiples of the median (MoM) or pregnancy-associated plasma protein A (PAPP-A) MoM were defined with ≥ 2.75 or ≤ 0.5, 7.72% (2,194/28,405) in the serum biochemical screening group and 12.36% (4,005/32,403) in CFTS group could be detected as abnormal results for further NIPS. Finally, 55.56% (5/9) and 85.71% (6/7) of trisomy 21 cases with false-negative results were detected, and the overall detection rate for trisomy 21 was improved by 10.64% (5/47) and 12.77% (6/47), respectively. CONCLUSIONS: The new contingent screening strategy can increase the detection rate of trisomy 21 compared with the traditional contingent screening strategy.

Comparing the results from a Swedish pregnancy cohort using data from three automated placental growth factor immunoassay platforms intended for first-trimester preeclampsia prediction.

INTRODUCTION: Risk evaluation for preeclampsia in early pregnancy allows identification of women at high risk. Prediction models for preeclampsia often include circulating concentrations of placental growth factor (PlGF); however, the models are usually limited to a specific PlGF method of analysis. The aim of this study was to compare three different PlGF methods of analysis in a Swedish cohort to assess their convergent validity and appropriateness for use in preeclampsia risk prediction models in the first trimester of pregnancy. MATERIAL AND METHODS: First-trimester blood samples were collected in gestational week 11+0 to 13+6 from 150 pregnant women at Uppsala University Hospital during November 2018 until November 2020. These samples were analyzed using the different PlGF methods from Perkin Elmer, Roche Diagnostics, and Thermo Fisher Scientific. RESULTS: There were strong correlations between the PlGF results obtained with the three methods, but the slopes of the correlations clearly differed from 1.0: PlGFPerkinElmer = 0.553 (95% confidence interval [CI] 0.518-0.588) * PlGFRoche -1.112 (95% CI -2.773 to 0.550); r = 0.966, mean difference -24.6 (95% CI -26.4 to -22.8). PlGFPerkinElmer = 0.673 (95% CI 0.618-0.729) * PlGFThermoFisher -0.199 (95% CI -2.292 to 1.894); r = 0.945, mean difference -13.8 (95% CI -15.1 to -12.6). PlGFRoche = 1.809 (95% CI 1.694-1.923) * PlGFPerkinElmer +2.010 (95% CI -0.877 to 4.897); r = 0.966, mean difference 24.6 (95% CI 22.8-26.4). PlGFRoche = 1.237 (95% CI 1.113-1.361) * PlGFThermoFisher +0.840 (95% CI -3.684 to 5.363); r = 0.937, mean difference 10.8 (95% CI 9.4-12.1). PlGFThermoFisher = 1.485 (95% CI 1.363-1.607) * PlGFPerkinElmer +0.296 (95% CI -2.784 to 3.375); r = 0.945, mean difference 13.8 (95% CI 12.6-15.1). PlGFThermoFisher = 0.808 (95% CI 0.726-0.891) * PlGFRoche -0.679 (95% CI -4.456 to 3.099); r = 0.937, mean difference -10.8 (95% CI -12.1 to -9.4). CONCLUSION: The three PlGF methods have different calibrations. This is most likely due to the lack of an internationally accepted reference material for PlGF. Despite different calibrations, the Deming regression analysis indicated good agreement between the three methods, which suggests that results from one method may be converted to the others and hence used in first-trimester prediction models for preeclampsia.

Motivation towards first trimester screening for preeclampsia among pregnant women in Denmark: A cross-sectional questionnaire study.

INTRODUCTION: The aim of this cross-sectional questionnaire study was to investigate motivation to participate in a possible new screening for preeclampsia in the first trimester of pregnancy among Danish pregnant women through a questionnaire based on Theory of Planned Behavior developed for this specific purpose. The new screening combines maternal characteristics with mean arterial pressure, uterine artery pulsatility index and biochemical markers to predict the risk of preeclampsia, whereas the current Danish screening uses maternal characteristics alone. MATERIAL AND METHODS: Participation was offered to a proportion of women attending a first or a second trimester screening scan at two University Hospitals in Copenhagen. The questionnaire was set up in REDCap® and answers were entered directly into the database, which was accessed via a QR-code. RESULTS: We invited 772 pregnant women to participate in the questionnaire survey between November 2021 and April 2022 at Copenhagen University Hospital Rigshospitalet (study site one) (n = 238) and Copenhagen University Hospital Hvidovre (study site two) (n = 534). The response rate was 71.8% (171/238) at study site one and 33.9% (181/534) at study site two. A total of 352 women were included in the study (total participation rate 45.6%). Most women had a positive attitude towards preeclampsia screening in pregnancy, and 99.4% said they would participate in a risk assessment for preeclampsia if given the opportunity. A total of 97.4% answered "yes" to whether a first trimester preeclampsia screening should be offered to all pregnant women in Denmark. Positive motivation to participate in preeclampsia screening was correlated with having a network with a positive attitude towards preeclampsia screening. CONCLUSIONS: The results of this study indicate that Danish pregnant women have a positive attitude towards participation in a first trimester screening for preeclampsia. This observation might be useful in relation to possible future implementation in Denmark.

First trimester serum apolipoproteins in the prediction of late-onset preeclampsia.

Late-onset preeclampsia occurring after 34 weeks of gestation is the most common form of preeclampsia, but little is known about either etiology or prevention. Current detection methods for preeclampsia in early pregnancy have not shown promising results in detecting late-onset preeclampsia. The aim of this study was to assess whether apolipoproteins in combination with maternal medical history and biophysical factors can be used as an early detection method for late-onset preeclampsia. This nested case-cohort study was based at Odense University Hospital, Denmark. Women attending their first trimester scan were invited to participate if they understood Danish or English, were above the age of 18, and had singleton pregnancies. Blood pressure, maternal medical history, uterine artery pulsatility indices, and blood samples were collected at inclusion. Outcome data were collected from participants' medical files postpartum, and cases were selected when preeclampsia diagnostics were present. Serum samples were analyzed by targeted mass spectrometry using a biomarker panel consisting of 12 apolipoproteins. Logistic regression analyses were performed and finally receiver operating curves were completed. The cohort consisted of 27 cases and 194 normotensive controls, randomized from 340 eligible participants. Significant differences were found between the two groups' baseline characteristics but none of the apolipoproteins showed significant difference (p < 0.05). The ROC-curve combining maternal characteristics, mean arterial pressure and two apolipoproteins showed the best sensitivity of 55.5% at a 10% false-positive rate and an area under the curve of 0.873. In conclusion, apolipoproteins did not improve the detection of late-onset preeclampsia in a combined screening model.

Follow Your Nose: Repeat Nasal Bone Evaluation in First-Trimester Screening for Down Syndrome.

OBJECTIVE: Examine whether repeat nasal bone evaluation following an absent/uncertain nasal bone on first-trimester screening (FTS) improves Down syndrome (DS) screening specificity. METHODS: A retrospective chart review of FTS sonograms in one center from January 2015 to January 2018 was performed. Data was extracted for those with an absent/uncertain nasal bone. Repeat evaluations were offered. RESULTS: Of 6780 FTS sonograms, 589 (8.7%) had an absent/uncertain nasal bone. Upon repeat exam, 268/376 (71.3%) had a present nasal bone. Compared with Black patients, patients of other ethnicities were more likely to have a present nasal bone on exam 2 (P < .00001). Of 268 patients with a present nasal bone on exam 2, 37 (13.8%) had an abnormal DS risk following exam 1; 34/37 (91.9%) normalized following nasal bone visualization, dropping the screen positive rate to 1.1%. CONCLUSION: Repeat nasal bone examination is beneficial in refining DS risk assessment and improves the specificity of FTS.