First-trimester Screening For Pre-eclampsia Research Articles

Placental growth factor at 24-28 weeks for aspirin discontinuation in pregnancies at high risk for preterm preeclampsia: Post hoc analysis of StopPRE trial.

This study aims to evaluate the safety of discontinuing aspirin treatment at 24-28 weeks in women at high risk after first-trimester combined screening for preeclampsia (PE) and normal placental growth factor (PlGF) levels at 24-28 weeks of gestation. This is a post hoc analysis of the StopPRE trial, conducted at nine Spanish maternity hospitals from September 2019 to September 2021. In the StopPRE trial, all high-risk single pregnancies identified during first-trimester screening for PE were treated with 150 mg of daily aspirin. Out of 1604 eligible women with a soluble fms-like tyrosine kinase-1 to PlGF ratio (sFlt-1/PlGF) ≤38 at 24-28 weeks, 968 were randomly assigned in a 1:1 ratio to either continue aspirin until 36 weeks (control group) or discontinue it (intervention group). In this secondary analysis, only women with PlGF ≥100 pg/mL at 24-28 weeks were included. As in the StopPRE trial, the non-inferiority margin was set at a 1.9% difference in preterm PE incidence between the groups. Among the 13 983 screened pregnant women, 1984 (14.2%) were deemed high-risk for preterm PE, of which 397 (20.0%) were ineligible, 636 declined participation, and 32 were excluded. Ultimately, 919 women with PlGF >100 pg/mL were randomized and included in this analysis. Preterm PE occurred in 0.9% of the intervention group (4 out of 465) and 1.5% of the control group (7 out of 454), indicating non-inferiority of aspirin discontinuation. There were no significant differences between the groups in adverse pregnancy outcomes before 37 weeks, at <34 weeks, or ≥37 weeks. Minor antepartum hemorrhage incidence was significantly lower in the intervention group (absolute difference, -5.96; 95% CI, -10.10 to -1.82). Discontinuation of aspirin treatment at 24-28 weeks in women with PlGF levels ≥100 pg/mL was non-inferior to continuing until 36 weeks for preventing preterm PE. However, these findings should be interpreted with caution, as they originate from a subanalysis of the StopPRE trial.

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

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. 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. 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. 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). 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.

Validation of machine-learning model for first-trimester prediction of pre-eclampsia using cohort from PREVAL study.

Effective first-trimester screening for pre-eclampsia (PE) can be achieved using a competing-risks model that combines risk factors from the maternal history with multiples of the median (MoM) values of biomarkers. A new model using artificial intelligence through machine-learning methods has been shown to achieve similar screening performance without the need for conversion of raw data of biomarkers into MoM. This study aimed to investigate whether this model can be used across populations without specific adaptations. Previously, a machine-learning model derived with the use of a fully connected neural network for first-trimester prediction of early (< 34 weeks), preterm (< 37 weeks) and all PE was developed and tested in a cohort of pregnant women in the UK. The model was based on maternal risk factors and mean arterial blood pressure (MAP), uterine artery pulsatility index (UtA-PI), placental growth factor (PlGF) and pregnancy-associated plasma protein-A (PAPP-A). In this study, the model was applied to a dataset of 10 110 singleton pregnancies examined in Spain who participated in the first-trimester PE validation (PREVAL) study, in which first-trimester screening for PE was carried out using the Fetal Medicine Foundation (FMF) competing-risks model. The performance of screening was assessed by examining the area under the receiver-operating-characteristics curve (AUC) and detection rate (DR) at a 10% screen-positive rate (SPR). These indices were compared with those derived from the application of the FMF competing-risks model. The performance of screening was poor if no adjustment was made for the analyzer used to measure PlGF, which was different in the UK and Spain. Therefore, adjustment for the analyzer used was performed using simple linear regression. The DRs at 10% SPR for early, preterm and all PE with the machine-learning model were 84.4% (95% CI, 67.2-94.7%), 77.8% (95% CI, 66.4-86.7%) and 55.7% (95% CI, 49.0-62.2%), respectively, with the corresponding AUCs of 0.920 (95% CI, 0.864-0.975), 0.913 (95% CI, 0.882-0.944) and 0.846 (95% CI, 0.820-0.872). This performance was achieved with the use of three of the biomarkers (MAP, UtA-PI and PlGF); inclusion of PAPP-A did not provide significant improvement in DR. The machine-learning model had similar performance to that achieved by the FMF competing-risks model (DR at 10% SPR, 82.7% (95% CI, 69.6-95.8%) for early PE, 72.7% (95% CI, 62.9-82.6%) for preterm PE and 55.1% (95% CI, 48.8-61.4%) for all PE) without requiring specific adaptations to the population. A machine-learning model for first-trimester prediction of PE based on a neural network provides effective screening for PE that can be applied in different populations. However, before doing so, it is essential to make adjustments for the analyzer used for biochemical testing. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

First trimester prediction models for small-for- gestational age and fetal growth restricted fetuses without the presence of preeclampsia

We established efficient first trimester prediction models for small-for-gestational age (SGA) and fetal growth restriction (FGR) without the presence of preeclampsia (PE) regardless of the gestational age of the onset of the disease [early FGR occurring before 32 gestational week or late FGR occurring after 32 gestational week]. The retrospective study was performed on singleton Caucasian pregnancies (n = 6440) during the period 11/2012–3/2020. Finally, 4469 out of 6440 pregnancies had complete medical records since they delivered in the Institute for the Care of Mother and Child, Prague, Czech Republic. The study included all cases diagnosed with SGA (n = 37) or FGR (n = 82) without PE, and 80 selected normal pregnancies. Four microRNAs (miR-1-3p, miR-20a-5p, miR-146a-5p, and miR-181a-5p) identified 75.68 % SGA cases at 10.0 % false positive rate (FPR). Eight microRNAs (miR-1-3p, miR-20a-5p, miR-20b-5p, miR-126-3p, miR-130b-3p, miR-146a-5p, miR-181a-5p, and miR-499a-5p) identified 83.80 % SGA cases at 10.0 % FPR. The prediction model for SGA based on microRNAs was further improved via implementation of maternal clinical characteristics [maternal age and BMI, an infertility treatment by assisted reproductive technology (ART), first trimester screening for PE and/or FGR and for spontaneous preterm, both by FMF algorithm]. Then 81.08 % and 89.19 % pregnancies developing SGA were identified at 10.0 % FPR in case of utilization of 4 microRNA and 8 microRNA biomarkers. Simplified prediction model for SGA based on limited number of maternal clinical characteristics (maternal age and BMI, an infertility treatment by ART, and 4 microRNAs) does not improve the detection rate of SGA (70.27 % SGA cases at 10.0 % FPR) when compared with prediction model for SGA based just on the expression profile of 4 or 8 microRNAs biomarkers. Seven microRNAs only (miR-16-5p, miR-20a-5p, miR-145-5p, miR-146a-5p, miR-181a-5p, miR-342-3p, and miR-574-3p) identified 42.68 % FGR cases at 10.0 % FPR (AUC 0.725). However, the combination of 10 microRNAs only (miR-16-5p, miR-20a-5p, miR-100-5p, miR-143-3p, miR-145-5p, miR-146a-5p, miR-181a-5p, miR-195-5p, miR-342-3p, and miR-574-3p) reached a higher discrimination power (AUC 0.774). It identified 40.24 % FGR cases at 10.0 % FPR. The prediction model for any subtype of FGR based on microRNAs was further improved via implementation of maternal clinical characteristics [maternal age and BMI, an infertility treatment by ART, the parity (nulliparity), the occurrence of SGA or FGR in previous gestation, and the occurrence of any autoimmune disorder, and the presence of chronic hypertension]. Then 64.63 % and 65.85 % pregnancies destinated to develop FGR were identified at 10.0 % FPR in case of utilization of 7 microRNA biomarkers or 10 microRNA biomarkers. When other clinical variables next to those ones mentioned above such as first trimester screening for PE and/or FGR and for spontaneous preterm, both by FMF algorithm, were added to the prediction model for FGR, the detection power was even increased to 74.39 % cases and 78.05 % cases at 10.0 % FPR.

OP19_5. First-trimester screening for preeclampsia and small-for-gestational-age: a comparison of the gaussian and FMF algorithms

OP19_5. First-trimester screening for preeclampsia and small-for-gestational-age: a comparison of the gaussian and FMF algorithms

OP09_4. Detection of false positives from first-trimester preeclampsia screening at the second-trimester of pregnancy (STOPPRE trial)

OP09_4. Detection of false positives from first-trimester preeclampsia screening at the second-trimester of pregnancy (STOPPRE trial)

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

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. 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. 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. 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.

Psychological Impact and Women's Evaluation of the First-Trimester Pre-Eclampsia Screening and Prevention: ASPRE Trial.

This study aims to extend the understanding of the psychological impact of the first-trimester pre-eclampsia (PE) screening on women identified as high risk for preterm PE. We examined the differences between low- vs. high-risk women throughout pregnancy in: symptoms of distress (anxiety, depression, physical and mental health, and worry), health behaviour changes, the experience of pregnancy, and attitudes towards PE screening. This study was nested within the ASPRE trial. Pregnant women were screened for preterm-PE risk status in the first trimester; the assessments were carried out before the screening, in the second and in the third trimester (n = 155 low-risk women and N = 82 high-risk women in the second trimester). The high-risk-for-PE women exhibited more depressive symptoms compared to the low-risk women in the second but not in the third trimester. No differences were observed between the two groups in other distress symptoms or in the women's evaluation of their experience of pregnancy. The high-risk group reported greater health behaviour changes compared to the low-risk group, but this was moderated by depression levels. Overall, pregnant women reported positive attitudes towards first-trimester PE screening, despite transient depressive symptoms. This study offers supportive evidence concerning the appropriateness of PE screening in ethical terms.

First-trimester preeclampsia screening and prevention: impact on patient satisfaction and anxiety

Preeclampsia affects between 2% and 5% of pregnant people in North America. First-trimester preeclampsia screening based on the Fetal Medicine Foundation risk calculation algorithm combined with treatment of high-risk patients with aspirin effectively reduces the incidence of preterm preeclampsia more than the currently used risk factor-based screening. However, the impact of such screening on patient satisfaction and maternal anxiety is unknown. This study aimed to assess the impact of first-trimester prediction and prevention of preterm preeclampsia on patient satisfaction and anxiety. Consenting pregnant patients participating in a local first-trimester (11-13+6 weeks) preterm preeclampsia screening and prevention implementation study1 were contacted 6 weeks postpartum to complete an online patient satisfaction survey, designed to assess their satisfaction with the screening program and their levels of trait anxiety (using an abbreviated version of the State-Trait Anxiety Inventory [STAIT-5]). In addition to assessing overall patient satisfaction, the level of patient satisfaction was stratified and compared according to levels of patient risk for preterm preeclampsia. Between June 2021 and December 2021, surveys were emailed to 765 participants. The response rate was 47.80% (358/765). Overall, 93% of participants reported high levels of satisfaction with preterm preeclampsia screening (70%-100%), and 98% stated that they would recommend the screening to all pregnant patients. With respect to levels of satisfaction with the program's support in reducing feelings of worry and anxiety, 87.9% of the total sample reported high satisfaction (70%-100%). The level of clinically significant symptoms of anxiety did not differ significantly between low- and high-risk groups (8% vs 10.8%, respectively). Overall, first-trimester preeclampsia screening was associated with high patient satisfaction and did not lead to differences in patient anxiety between those with high- and low-risk screen results.

Prenatal screening for preeclampsia: the roles of placental growth factor and pregnancy–associated plasma protein A in the first trimester and placental growth factor and soluble fms-like tyrosine kinase 1–placental growth factor ratio in the early second trimester

Professional societies have recommended universal first trimester screening for preeclampsia and a second or third trimester soluble fms-like tyrosine kinase-1-placental growth factor ratio test to assess for preeclampsia and its severity. However, it may not be feasible to implement the most optimal screening protocol for preeclampsia in the first trimester which uses a combination of maternal characteristics, maternal biophysical and biochemical markers due to limitations in the access to uterine artery doppler ultrasound. There are inconsistent findings on how early in the second trimester the fms-like tyrosine kinase-1-placental growth factor ratio begins to provide useful information in preeclampsia prediction. This study aimed to assess the accuracy of (1) a combination of maternal characteristics, maternal serum pregnancy-associated plasma protein A, and placental growth factor in the screening for preeclampsia in the first trimester; and (2) placental growth factor or soluble fms-like tyrosine kinase-1-placental growth factor ratio in the prediction of preeclampsia in the early second trimester. This retrospective case-control study used frozen residual blood samples from women who had aneuploidy screening and delivered at a tertiary center. The case group included pregnancies with gestational hypertension or preeclampsia (further classified as early-onset [birth at <34 weeks' gestation] and preterm preeclampsia [birth at <37 weeks' gestation]). Each case was matched with 3 control pregnancies by date of blood sample draw, gestational age at first blood sample draw, maternal age, maternal ethnicity, type of multiple-marker screening, and amount of residual sample. Mann-Whitney U tests were used to assess the associations between serum markers and the risk of preeclampsia. Logistic regressions were used to assess if the risk of preeclampsia can be predicted using a combination of maternal characteristics and serum markers. The case group included 146 preeclampsia and 295 gestational hypertension cases. Compared with the controls, preeclampsia cases had significantly lower first-trimester pregnancy-associated plasma protein A and placental growth factor. At a 20% false-positive rate, 71% of early-onset and 58% of preterm preeclampsia cases can be predicted using maternal characteristics, pregnancy-associated plasma protein A, and placental growth factor. Preeclampsia cases had lower second-trimester placental growth factor and a higher soluble fms-like tyrosine kinase-1-placental growth factor ratio. At a 10% false-positive rate, 80% and 53% of early-onset preeclampsia can be predicted using maternal characteristics and placental growth factor or soluble fms-like tyrosine kinase-1-placental growth factor ratio, respectively. The current first-trimester aneuploidy screening programs may be expanded to identify women at increased risk of developing preeclampsia. Early in the second trimester, placental growth factor alone provided better prediction for preeclampsia compared with the soluble fms-like tyrosine kinase-1-placental growth factor ratio.

Reviewing Accuracy of First Trimester Screening for Preeclampsia Using Maternal Factors and Biomarkers.

Preeclampsia is a common and important complication of pregnancy, one with potentially significant morbidity and even mortality to both mother and baby. Identifying those at high risk of developing the condition is helpful as there is evidence that the incidence of preeclampsia can be reduced with low dose aspirin taken in pregnancy. Accurately predicting the risk of preeclampsia allows for more targeted aspirin prophylaxis and a greater opportunity for early detection of maternal and/or fetal complications associated with impaired placentation through a schedule of enhanced antenatal surveillance. Traditional preeclampsia prediction models use maternal characteristics and risk factors and have been shown to be of low predictive value. Multiparametric screening tests combine patient characteristics with serum biomarkers and ultrasound Doppler indices and have been shown to be more effective at detecting those at high risk of preeclampsia – more specifically, early-onset preeclampsia (onset of preeclampsia <34 weeks’ gestation). Multiparametric screening has now been validated in different populations. The true cost effectiveness of a multiparametric screening model for preeclampsia screening is not yet fully known and will vary depending on the clinical setting. Despite the growing body of evidence for its improved detection rates, first trimester preeclampsia screening using multiparametric models is not widely implemented and is not part of the recommendations for antenatal screening from most international bodies. The International Federation of Gynecology and Obstetrics has advised universal preeclampsia screening using maternal risk factors and biomarkers and has strongly encouraged its promotion worldwide. Various barriers to implementation must be considered such as the immediate cost of equipment and training, the need for audit and quality control, and the expected benefit to the population. Low to middle income settings may require a pragmatic approach to the implementation of multiparametric screening given limited resources.

Prediction of spontaneous preterm birth and preterm prelabor rupture of membranes using maternal factors, obstetric history and biomarkers of placental function at 11-13 weeks.

To determine whether first-trimester biomarkers of placental function can be used to screen for spontaneous preterm birth (sPTB), and to develop prediction models using maternal factors, obstetric history and biomarkers of placental function at 11-13 weeks for the calculation of patient-specific risk for sPTB. This was a retrospective secondary analysis of data derived from a prospective cohort study on first-trimester screening for pre-eclampsia in singleton pregnancies attending for routine Down syndrome screening at 11 + 0 to 13 + 6 weeks' gestation at a tertiary obstetric unit between December 2016 and September 2019. A split-sample internal validation method was used to explore and develop prediction models for all sPTB at < 37 weeks and for PTB at < 37 weeks after preterm prelabor rupture of membranes (PPROM) using maternal risk factors, uterine artery Doppler indices, serum placental growth factor (PlGF), pregnancy-associated plasma protein-A (PAPP-A) and β-human chorionic gonadotropin (β-hCG). Screening performance was assessed using receiver-operating-characteristics (ROC)-curve analysis, with calculation of the areas under the ROC curves (AUCs). A total of 9298 singleton pregnancies were included in this study. sPTB at < 37 weeks occurred in 362 (3.89%) cases, including 231 (2.48%) cases of PPROM. sPTB at < 34 weeks occurred in 87 (0.94%) cases, including 39 (0.42%) cases of PPROM. Identified maternal risk factors for sPTB at < 37 weeks included chronic hypertension, conception using in-vitro fertilization and history of PTB. Maternal risk factors for PPROM at < 37 weeks included conception using in-vitro fertilization and history of PTB. Median PlGF multiples of the median (MoM) and PAPP-A MoM were significantly reduced in women with sPTB at < 37 weeks, as well as in those who had PPROM, compared to those who delivered at term. Screening by a combination of maternal risk factors, PAPP-A and PlGF achieved better performance in predicting sPTB at < 37 weeks (AUC, 0.630 vs 0.555; detection rate (DR), 24.8% vs 16.6% at a false-positive rate (FPR) of 10%; P ≤ 0.0001) and PPROM at < 37 weeks (AUC, 0.643 vs 0.558; DR, 28.1% vs 17.0% at a FPR of 10%; P ≤ 0.0001) than using maternal risk factors alone. Both models were successfully applied to the internal validation dataset, with AUCs of 0.628 and 0.650, respectively. We demonstrated that low levels of maternal serum PAPP-A and PlGF in the first trimester are associated with increased risks of sPTB and PPROM at < 37 weeks. However, further research is needed to identify additional biomarkers to improve the screening performance of the combined model that includes maternal risk factors, PAPP-A and PlGF before clinical application. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.

Integrating Combined First Trimester Screening for Preeclampsia into Routine Ultrasound Examination.

Introduction The Fetal Medicine Foundation (FMF) London has developed a first trimester screening algorithm for preeclampsia (PE), based on maternal characteristics and past risk factors, mean arterial pressure (MAP), uterine artery pulsatility index (UtA-PI), and placental growth factor (PlGF). The aim of this study was to determine the feasibility of integrating PE screening into routine practice. Material and Methods All pregnancies with a fetal crown-rump length of 45 – 84 mm presenting to our ultrasound department between January 2014 and September 2020 were included in this analysis. Screening for PE was offered to singleton pregnancies only. The number of screening tests performed in the eligible population was assessed and the reasons for missed screenings identified with the help of the electronic clinical database. SPSS Statistics 25 and GraphPad version 8.0 for Windows were used for statistical analysis. Results 6535 pregnancies were included, 4510 (69.0%) of which were screened for PE. The percentage of patients being offered PE screening increased over the years from 63.1 to 96.7% (r s = 0.96; p = 0.003), while the rate of screenings performed in eligible patients remained stable at a median [range] of 86.2% [78.0 – 91.8%] (p = ns). 2025 (31.0%) pregnancies were not screened for PE, 1306 (64.5%) because they were not eligible for screening. 145 (2.2%) women explicitly declined PE screening; their background risk was lower than that of women who accepted screening. Conclusion Our study shows that integration of PE screening into the routine first trimester ultrasound scan is feasible and widely accepted by pregnant women and health care providers.

Maternal serum pregnancy-associated plasma protein-A concentration at 11–14 weeks of gestation and preeclampsia risk of women with common congenital anatomic uterine abnormalities

To evaluate maternal serum pregnancy-associated plasma protein-A (PAPP-A) levels at 11–14 weeks of gestation and preeclampsia risk in women with common congenital anatomic uterine abnormalities (AUAs). First trimester screening markers were compared between 12 AUA pregnancies, 60 age matched controls and 12 cases of early preeclampsia. PAPP-A level and birth weight were significantly lower in AUA compared to control and early preeclampsia group (p<.001). Preeclampsia was absent in the AUAs pregnancies group. Birth weight were similar in AUA group when we compared AUA and control group regarding weeks of gestation at delivery and lower but not significantly, when we compared AUA and early preeclampsia group. Our findings suggest that AUA pregnancies are associated with low first trimester maternal serum PAPP-A concentrations not predictive of susceptibility to preeclampsia. Impact statement What is already known on this subject? During first trimester screening for preeclampsia based on maternal pregnancy-associated plasma protein A (PAPP-A) levels, various parameters are used, such as the somatometric characteristics of pregnant woman, single or multiple pregnancy, smoking status, family history, diabetes, hypertension and measurement of blood pressure and uterine artery Dopplers. What do the results of this study add? Our pioneer study revealed that there is drastic difference in PAPP-A concentration in women with common anatomic uterine abnormalities (AUAs), in comparison with their age matched control women with normal uterus. What are the implications of these findings for clinical practice and further research? Based on our results, uterine anatomical deviations, is another factor which must be taken in account for preeclampsia risk calculation and further clinical consultation and follow up in those pregnancies. Lower PAPP-A levels in AUA cases is a weak predictor of susceptibility to preeclampsia and could be associated to smaller placental size rather than poor placentation and in future research the calculation of the uterine cavity functional dimension may lead to a more accurate clinical assessment.

Cardiovascular Disease-Associated MicroRNA Dysregulation during the First Trimester of Gestation in Women with Chronic Hypertension and Normotensive Women Subsequently Developing Gestational Hypertension or Preeclampsia with or without Fetal Growth Restriction.

The aim of the study was to assess if cardiovascular disease-associated microRNAs would be able to predict during the early stages of gestation (within 10 to 13 weeks) subsequent onset of hypertensive pregnancy-related complications: gestational hypertension (GH) or preeclampsia (PE). Secondly, the goal of the study was to assess if cardiovascular disease-associated microRNAs would be able to detect the presence of chronic hypertension in early pregnancies. The retrospective study was performed on whole peripheral blood samples collected from singleton Caucasian pregnancies within the period November 2012 to March 2020. The case control study, nested in a cohort, involved all women with chronic hypertension (n = 29), all normotensive women that later developed GH (n = 83) or PE with or without fetal growth restriction (FGR) (n = 66), and 80 controls selected on the base of equal sample storage time. Whole peripheral blood profiling was performed with the selection of 29 cardiovascular disease-associated microRNAs using real-time RT-PCR. Upregulation of miR-1-3p (51.72% at 10.0% FPR) was observed in patients with chronic hypertension only. Upregulation of miR-20a-5p (44.83% and 33.33% at 10.0% FPR) and miR-146a-5p (65.52% and 42.42% at 10.0% FPR) was observed in patients with chronic hypertension and normotensive women with later occurrence of PE. Upregulation of miR-181a-5p was detected in normotensive women subsequently developing GH (22.89% at 10.0% FPR) or PE (40.91% at 10.0% FPR). In a part of women with subsequent onset of PE, upregulation of miR-143-3p (24.24% at 10.0% FPR), miR-145-5p (21.21% at 10.0% FPR), and miR-574-3p (27.27% at 10.0% FPR) was also present. The combination of microRNA biomarkers (miR-20a-5p, miR-143-3p, miR-145-5p, miR-146a-5p, miR-181a-5p, and miR-574-3p) can predict the later occurrence of PE in 48.48% of pregnancies at 10.0% FPR in early stages of gestation. The combination of upregulated microRNA biomarkers (miR-1-3p, miR-20a-5p, and miR-146a-5p) is able to identify 72.41% of pregnancies with chronic hypertension at 10.0% FPR in early stages of gestation. Cardiovascular disease-associated microRNAs represent promising biomarkers with very good diagnostical potential to be implemented into the current first trimester screening program to predict later occurrence of PE with or without FGR. The comparison of the predictive results of the routine first trimester screening for PE and/or FGR based on the criteria of the Fetal Medicine Foundation and the first trimester screening for PE wo/w FGR using a panel of six cardiovascular disease-associated microRNAs only revealed that the detection rate of PE increased 1.45-fold (48.48% vs. 33.33%).

Reducing the Risk of Preterm Preeclampsia: Comparison of Two First Trimester Screening and Treatment Strategies in a Single Centre in Switzerland.

Introduction First trimester screening for preeclampsia (PE) is based on the combined risks model. Recent trials demonstrate that variations in multiple of the medians (MoMs) of the screening markers influence the performance of the algorithm in different populations. The aim of this study is to compare the performance of the algorithm in two cohorts with different prevention strategies. Material and Methods All first trimester screening tests performed between January 2014 and April 2020 were included. Up to June 2017 pregnancies with a risk > 1 : 200 for early-onset PE (eoPE) were considered at risk and received 100 mg of aspirin (strategy A). From July 2017 onwards, pregnancies with a risk > 1 : 100 for preterm PE (pPE) received 150 mg of aspirin (strategy B). We compared the screen positive rates (SPR) and incidence of PE between the two screening approaches. Statistical analysis were performed with Graphpad 8.0. Results 3552 pregnancies were included; 1577 pregnancies were screened according to strategy A, 1975 pregnancies according to strategy B. The screen positive rate (SPR) for strategy A and B was 8.9 and 16.9% respectively (p < 0.0001) while the incidence of PE was 1.41 and 1.84% respectively (p = ns). Conclusion With a SPR of less than 10% we achieved a remarkably low rate of PE in our population, no further reduction in PE could be achieved by an increase in the SPR and LDA-prescription during the second screening period. The cut-off to define a pregnancy at risk for PE should be tailored to keep the SPR below 10% to avoid unnecessary treatment with aspirin.

Cost-effectiveness analysis of first trimester screening for preeclampsia and early initiation of aspirin therapy for prevention of the disease in a private tertiary hospital

Background: Preeclampsia (PE) has significant health and economic burden. Early screening for PE through first trimester screening (FTS) can direct decision-making on early initiation of aspirin (ASA) therapy, which has been known to reduce the incidence of PE. Objectives: The objective of the study is to evaluate the cost-effectiveness of FTS and early initiation of ASA for disease prevention. Methodology: A population of 1916 women who delivered in a private tertiary hospital from January 2019 to March 2020 was categorized based on the risk of developing PE, results of FTS, initiation of ASA therapy, development of PE, and mode of delivery. Descriptive statistics using counts and percentages were used to summarize the data. Association between ASA therapy and PE was assessed using the Chi-square test. Costs of screening, ASA therapy, inpatient management, and delivery were computed. Results and Conclusion: Results showed that PE was prevented in 71.4% of those high-risk patients who underwent FTS and started on ASA therapy. Total cost of urgent care of PE and delivery was P119,687.02 to P149,687.02 for early PE, and P103,587.02 to P133,587.02 for late PE. Prevention of early PE and late PE results in net cost savings of P69,694.02 and P53,594.02, respectively, with the investment of P9,993.00 on FTS and ASA therapy. Implementation of FTS and initiation ASA therapy is an effective and cost-saving approach that can prevent PE.

Early Prophylactic Enoxaparin for the Prevention of Preeclampsia and Intrauterine Growth Restriction: A Randomized Trial

Background: Preeclampsia (PE) and intrauterine growth restriction (IUGR) are major causes of maternal and perinatal morbidity and mortality. Previous studies have shown that intervention with low-dose aspirin resulted in a reduction in the occurrence of preterm PE. However, no data are currently available on the effect of low-molecular-weight heparin (LMWH) for the prevention of pregnancy complications in women enrolled at first trimester screening. Objective: We aimed to assess the effectiveness of LMWH in the prevention of PE, IUGR, fetal death, and abruptio placentae in women classified as high risk based on their medical history and in women selected by first trimester screening of PE. Study ­Design: This was a multicenter, randomized, open-label, parallel controlled trial in women without thrombophilia between 6.0 and 15.6 weeks of gestation. Inclusion criteria were severe PE or IUGR before 34 weeks of gestation and/or abruptio placentae or unexplained intrauterine death in a previous pregnancy; uterine artery mean pulsatility index Doppler >95th percentile and/or positive first trimester screening for PE. Pregnant women were randomly assigned to receive no intervention or LMWH until the 36th week of gestation. The primary composite outcome consisted of 1 or more of the following: development of PE, IUGR, abruptio placentae, and intrauterine fetal death. Results: A total of 278 pregnant women were randomly allocated to receive LMWH (n = 134) or no intervention (n = 144). Overall, 115 (41%) women experienced placental insufficiency complications, with no significant differences between the 2 arms: 50/144 (34.7%) in the LMWH arm and 43/134 (32%) in the control arm (p = 0.64, OR: 1.13, 95% CI: 0.68–1.85). Conclusion: LMWH did not reduce the incidence of placenta-mediated complications either in women with previous adverse obstetric history without thrombophilia or in women selected by first trimester screening for PE. Based on these results, we cannot recommend the use of LMWH alone in women at risk of placental complications.

The need for implementation of first trimester screening for preeclampsia and fetal growth restriction in low resource settings

Background Preeclampsia [PE] and fetal growth restriction [FGR] is a major cause of perinatal morbidity in both developed and developing countries but the disease leaves a severe impact in developing countries, due to the late presentation of cases where prevention and treatment becomes impossible. Routine antenatal ultrasound and health checkups in periphery are usually done in first trimester for dating and viability scan, in midtrimester for anomaly scan and in third trimester for safe confinement. Underlying disorder of deep placentation which is unidentified can lead to increased maternal morbidity and fetal compromise between 26 to 34 weeks of gestation The complications present at an irreversible stage where there is no sufficient time even for referral to tertiary care center. Frequent antenatal visits as suggested by WHO would definitely bring down maternal mortality but this increased surveillance when offered to all might be a huge burden to health care providers in low resource settings. An acceptable screening test should help in triaging the high risk group in first trimester itself targeting about only one third of the population for prophylactic therapy and increased antenatal surveillance.The objective of this study is to evaluate the performance and feasibility of different screening protocols in low resource settings. Methodology Screening for PE and FGR was done at the 11–14 weeks aneuploidy scan as per FMF guidelines. Group I included 6289 women whose risk prediction was done with maternal characteristics [MC], mean arterial pressure [MAP] and Uterine artery Doppler [UAD]. Group II included 2067 women whose risk was predicted with MC, MAP, UAD and PAPP-A. Group III included 576 women whose risk prediction included all parameters with PLGF. Results Two thousand five hundred fifty-seven cases were screen positive in group I and 602 were screen positive in group II. In group III which included PLGF, 24 were positive for early onset PE and 36 for late onset PE. The number needed to treat [NNT] was 35.9, 29.1 and 10% in Group I, II and III respectively. The detection rate [DR] for PE and FGR was 60% in Group I and DR for FGR in Group II was 85%. In Group III, for early onset PE the DR was 98% and 68% for late onset PE. Conclusion Screening for PE with available resources in the periphery needs to be implemented to avoid its grave complications. Traditional screening for PE by NICE guidelines can be adopted but may have a detection rate of only 30–40%. Though screening by ACOG criteria may have good detection rates but more than two thirds of the population would become screen positive which nullifies this approach as a good screening methodology in low resource settings. Multiparametric approach for screening in first trimester serves as a better screening tool to enable higher detection rate of disease with least false positive rates. Uterine artery Doppler when combined with maternal characteristics and mean arterial pressure could achieve a detection rate of about 60% and would still target only one third of the population for increased antenatal surveillance. This requires training healthcare professionals in the periphery for this approach and this should be our prime focus in the current scenario. Inclusion of serum biochemistry would still bring down the target population to 10% and increase the DR and can be considered as an additional test in economically feasible population. In low resource settings a better screening approach to PE would be a combination of maternal history, biophysical or biochemical parameters whichever is feasible considering the economy and availability of resources.

Effect of Low-Dose Aspirin on Soluble FMS-Like Tyrosine Kinase 1/Placental Growth Factor (sFlt-1/PlGF Ratio) in Pregnancies at High Risk for the Development of Preeclampsia.

Background: Soluble FMS-like Tyrosine Kinase 1 (sFlt-1) and placental growth factor (PlGF) have been reported to be highly predictive several weeks before the onset of preeclampsia. Objective: To investigate longitudinal changes of serum levels sFlt-1 and PlGF in pregnant women at high risk for the development of preeclampsia and to reveal an impact of aspirin on maternal serum concentrations of sFlt-1 and PlGF. Methods: This was a prospective longitudinal study in 394 women with various risk factors for the development of preeclampsia (chronic hypertension, antiphospholipid syndrome/APS or systemic lupus erythematosus/SLE, thrombophilia, women with a history of preeclampsia, pathologic first trimester screening for preeclampsia) and 68 healthy women. Serum levels of sFlt-1 and PlGF were measured prospectively at 4-week intervals (from gestational weeks 12 until postpartum). Results: The sFlt-1/PlGF ratio was significantly higher in women with an adverse obstetric outcome compared to women with a normal pregnancy, starting between 20 and 24 weeks of gestation. There was no effect of aspirin on sFlt-1/PlGF ratio in women with chronic hypertension, APS/SLE, thrombophilia and controls. The use of aspirin showed a trend towards an improvement of the sFlt-1/PlGF ratio in women with preeclampsia in a previous pregnancy and a significant effect on the sFlt-1/PlGF ratio in women with a pathologic first trimester screening for preeclampsia. Conclusions: Our findings reveal an impact of aspirin on sFlt-1/PlGF ratio in women with a pathologic first trimester screening for preeclampsia, strongly supporting its prophylactic use.