Fetal Medicine Foundation Algorithm Research Articles

Prospective Validation of First-Trimester Screening for Preterm Preeclampsia in Nulliparous Women (PREDICTION Study).

Fetal Medicine Foundation (FMF) studies suggest that preterm preeclampsia can be predicted in the first trimester by combining biophysical, biochemical, and ultrasound markers and prevented using aspirin. We aimed to evaluate the FMF preterm preeclampsia screening test in nulliparous women. We conducted a prospective multicenter cohort study of nulliparous women recruited at 11 to 14 weeks. Maternal characteristics, mean arterial blood pressure, PAPP-A (pregnancy-associated plasma protein A), PlGF (placental growth factor) in maternal blood, and uterine artery pulsatility index were collected at recruitment. The risk of preterm preeclampsia was calculated by a third party blinded to pregnancy outcomes. Receiver operating characteristic curves were used to estimate the detection rate (sensitivity) and the false-positive rate (1-specificity) for preterm (<37 weeks) and for early-onset (<34 weeks) preeclampsia according to the FMF screening test and according to the American College of Obstetricians and Gynecologists criteria. We recruited 7554 participants including 7325 (97%) who remained eligible after 20 weeks of which 65 (0.9%) developed preterm preeclampsia, and 22 (0.3%) developed early-onset preeclampsia. Using the FMF algorithm (cutoff of ≥1 in 110 for preterm preeclampsia), the detection rate was 63.1% for preterm preeclampsia and 77.3% for early-onset preeclampsia at a false-positive rate of 15.8%. Using the American College of Obstetricians and Gynecologists criteria, the equivalent detection rates would have been 61.5% and 59.1%, respectively, for a false-positive rate of 34.3%. The first-trimester FMF preeclampsia screening test predicts two-thirds of preterm preeclampsia and three-quarters of early-onset preeclampsia in nulliparous women, with a false-positive rate of ≈16%. URL: https://www.clinicaltrials.gov; Unique identifier: NCT02189148.

Performance of the first-trimester Fetal Medicine Foundation competing risks model for preeclampsia prediction: an external validation study in Brazil

Background: The current version of the Fetal Medicine Foundation competing risks model for preeclampsia prediction has not been previously validated in Brazil.Objectives: (1) To validate the Fetal Medicine Foundation combined algorithm for the prediction of preterm preeclampsia in the Brazilian population and (2) to describe the accuracy and calibration of the Fetal Medicine Foundation algorithm when considering the prophylactic use of aspirin, by clinical criteria.Study design: Cohort study, including consecutive singleton pregnancies undergoing preeclampsia screening at 11-14 weeks, examining maternal characteristics, medical history, and biophysical markers between October 2010 and December 2018 in a university hospital in Brazil. Risks were calculated using the 2018 version of the algorithm available on the Fetal Medicine Foundation website, and cases were classified as low- or high-risk using cut-off of 1/100 to evaluate predictive performance. Expected and observed cases with PE according to the FMF estimated risk range (≥1 in 10; 1 in 11 to 1 in 50; 1 in 51 to 1 in 100; 1 in 101 to 1 in 150; and <1 in 150) were compared. After identifying high-risk pregnant women who used aspirin, the treatment effect of 62% reduction in preterm preeclampsia identified in the ASPRE trial was used to evaluate the predictive performance adjusted for the effect of aspirin. The number of potentially unpreventable cases in the group without aspirin use was estimated.Results: Among 2,749 pregnancies, preterm preeclampsia occurred in 84 (3.1%). With a risk cut-off of 1/100, the screen-positive rate was 25.8%. The detection rate was 71.4%, with a false positive rate of 24.4%. The area under the curve was 0.818 (95% confidence interval 0.773 to 0.863). In the risk range ≥1/10, there is an agreement between the number of expected and observed cases, and in the other ranges, the predicted risk was lower than the observed rates. Accounting for the effect of aspirin resulted in an increase in detection rate and positive predictive values and a slight decrease in the false positive rate. With 27 cases of preterm preeclampsia in the high-risk group without aspirin use, we estimate that 16 of these cases of preterm preeclampsia would have been avoided if this group had received prophylaxis.Conclusions: In a high prevalence setting, the Fetal Medicine Foundation algorithm can identify women who are more likely to develop preterm preeclampsia. Not accounting for the effect of aspirin underestimates the screening performance.

Routine first-trimester pre-eclampsia screening and maternal left ventricular geometry.

Pre-eclampsia (PE) is a pregnancy complication associated with premature cardiovascular disease morbidity and mortality (i.e. before 60 years of age or in the first year postpartum). PE is associated with adverse left ventricular (LV) remodeling in the peri- and postpartum periods, an independent risk factor for cardiovascular disease. This study aimed to compare LV geometry by LV mass (LVM) and LVM index (LVMI) between participants with a high vs low screening risk for preterm PE in the first trimester. This was a prospective cohort study of singleton pregnancies between 11 + 0 and 13 + 6 weeks' gestation that underwent screening for preterm PE as part of their routine first-trimester ultrasound assessment at a tertiary center in London, UK, from February 2019 until March 2020. Screening for preterm PE was performed using the Fetal Medicine Foundation algorithm. Participants with a screening risk of ≥ 1 in 50 for preterm PE were classified as high risk and those with a screening risk of ≤ 1 in 500 were classified as low risk. All participants underwent two-dimensional and M-mode transthoracic echocardiography. A total of 128 participants in the first trimester of pregnancy were included in the analysis, with 57 (44.5%) participants screened as low risk and 71 (55.5%) participants as high risk for PE. The risk groups did not vary in maternal age and gestational age at assessment. Maternal body surface area and body mass index were significantly higher in the high-risk group (all P < 0.05). The high-risk participants were significantly more likely to be Afro-Caribbean, nulliparous and have a family history of hypertensive disease in pregnancy as well as other cardiovascular disease (all P < 0.05). In addition, mean arterial blood pressure (P < 0.001), mean heart rate (P < 0.001), median LVM (130.06 (interquartile range, 113.62-150.50) g vs 97.44 (81.68-114.16)g; P < 0.001) and mean LVMI (72.87 ± 12.2 g/m2 vs 57.54 ± 12.72 g/m2 ; P < 0.001) were significantly higher in the high-risk group. Consequently, those in the high-risk group were more likely to have abnormal LV geometry (37.1% vs 7.0%; P < 0.001). Early echocardiographic assessment in participants at high risk of preterm PE may unmask clinically healthy individuals who are at increased risk for future cardiovascular disease. Adverse cardiac remodeling in the first trimester of pregnancy may be an indicator of decreased cardiovascular reserve and subsequent dysfunctional cardiovascular adaptation in pregnancy. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Aspirin for evidence-based preeclampsia prevention trial: effects of aspirin on maternal serum pregnancy-associated plasma protein A and placental growth factor trajectories in pregnancy

BackgroundThe exact mechanism by which aspirin prevents pre-eclampsia (PE) remains unclear. Its effects on serum placental biomarkers throughout pregnancy are also unknown. ObjectiveTo investigate the effects of aspirin on serum pregnancy-associated plasma protein A (PAPP-A) and placental growth factor (PlGF) trajectories using repeated measures from women at increased risk of preterm PE. Study DesignThis was a longitudinal secondary analysis of the Combined Multimarker Screening and Randomized Patient Treatment with Aspirin for Evidence-based Preeclampsia Prevention (ASPRE) trial using repeated measures of PAPP-A and PlGF. In the trial, 1,620 women at increased risk of preterm PE were identified using the Fetal Medicine Foundation algorithm at 11-13+6 weeks, of whom 798 were randomly assigned to receive aspirin 150 mg and 822 to receive placebo daily from before 14 weeks to 36 weeks of gestation. Serum biomarkers were measured at baseline and follow-up visits at 19 to 24, 32 to 34, and 36 weeks of gestation. Generalized additive mixed models with treatment by gestational age interaction terms were used to investigate the effect of aspirin on biomarker trajectories over time. ResultsOverall, there were 5,507 PAPP-A and 5,523 PlGF measurements. Raw PAPP-A values increased over time, and raw PlGF increased until 32 weeks of gestation followed by a decline. The multiple of the median (MoM) mean values of the same biomarkers were consistently below 1.0 MoM, reflecting the high-risk profile of the study population. Trajectories of mean PAPP-A and PlGF MoM values did not differ significantly between the aspirin and placebo groups (aspirin treatment by gestational age interaction p-values: 0.259 and 0.335, respectively). ConclusionsIn women at increased risk of preterm PE, aspirin 150 mg daily had no significant effects on PAPP-A or PlGF trajectories when compared to placebo.

Trisomy 21 screening with αlpha software and the Fetal Medicine Foundation algorithm

Background. Screening for trisomy 21 provides pregnant women with accurate risk information. Different algorithms are used to screen for trisomy 21 in South Africa (SA). The Fetal Medicine Foundation (FMF) provides software to screen for trisomy 21 in the first trimester by ultrasound or a combination of ultrasound and biochemistry (combined screening), and requires regular and stringent quality control. With αlpha software, first trimester combined screening and screening with biochemistry alone in the first or second trimester are possible. The αlpha screening requires quality control of biochemical tests, but not of ultrasound measurements. Ideally, a screening test should have a high detection and a low screen positive rate. Despite the availability of these screening programmes, only a minority of infants with trisomy 21 are detected prenatally, raising questions about the effectiveness of screening. Objectives. To determine the screen positive and detection rates of prenatal screening for trisomy 21 in the SA private healthcare system. Methods. Data from the three largest laboratories collected between 2010 and 2015 were linked with genetic tests to assess screen positive and detection rates. Biochemical screening alone with αlpha software (first or second trimester) and combined screening using either FMF or αlpha software were compared. Results. One-third of an estimated 675 000 pregnancies in private practice in the 6-year study period underwent screening. There were 687 cases of trisomy 21 in 225 021 pregnancies, with only 239 (35%) diagnosed prenatally. The screen positive rates were 11.8% for first trimester biochemistry, 7.6% for second trimester biochemistry, 7.3% for first trimester FMF software ultrasound alone, 3.7% for combined first trimester screening with FMF software, and 3.5% for combined first trimester screening with αlpha software. The detection rates for a 5% false positive rate were 63% for first trimester biochemistry, 69% for second trimester biochemistry, 95% for combined first trimester screening with FMF software and 80% for combined first trimester screening with αlpha software. Detection and confirmation rates were highest with FMF software. Conclusion. Screening with FMF software has a similar screen positive rate and better detection rate than screening with αlpha software. The low prenatal detection rate of trisomy 21 is mainly due to a low prevalence of screening. More research is needed in the SA setting to explore why screening and confirmatory testing after high-risk results are not performed in many pregnancies.

First trimester screening for pre-eclampsia and targeted aspirin prophylaxis: a cost-effectiveness cohort study.

Investigate cost-effectiveness of first trimester pre-eclampsia screening using the Fetal Medicine Foundation (FMF) algorithm and targeted aspirin prophylaxis in comparison with standard care. Retrospective observational study. London tertiary hospital. 5957 pregnancies screened for pre-eclampsia using the National Institute for Health and Care Excellence (NICE) method. Differences in pregnancy outcomes between those who developed pre-eclampsia, term pre-eclampsia and preterm pre-eclampsia were compared by the Kruskal-Wallis and Chi-square tests. The FMF algorithm was applied retrospectively to the cohort. A decision analytic model was used to estimate costs and outcomes for pregnancies screened using NICE and those screened using the FMF algorithm. The decision point probabilities were calculated using the included cohort. Incremental healthcare costs and QALY gained per pregnancy screened. Of 5957 pregnancies, 12.8% and 15.9% were screen-positive for development of pre-eclampsia using the NICE and FMF methods, respectively. Of those who were screen-positive by NICE recommendations, aspirin was not prescribed in 25%. Across the three groups, namely, pregnancies without pre-eclampsia, term pre-eclampsia and preterm pre-eclampsia there was a statistically significant trend in rates of emergency caesarean (respectively 21%, 43% and 71.4%; P < 0.001), admission to neonatal intensive care unit (NICU) (5.9%, 9.4%, 41%; P < 0.001) and length of stay in NICU. The FMF algorithm was associated with seven fewer cases of preterm pre-eclampsia, cost saving of £9.06 and QALY gain of 0.00006/pregnancy screened. Using a conservative approach, application of the FMF algorithm achieved clinical benefit and an economic cost saving.

First-trimester screening for Down syndrome using quadruple maternal biochemical markers.

Placental growth factor (PlGF) is used for first-trimester preeclampsia screening and could be combined with other biochemical markers for Down syndrome screening. We aim to estimate the predictive value of the combination of pregnancy-associated plasma protein (PAPP-A), free β-human chorionic gonadotropin (free β-hCG), placental growth factor (PlGF) and α-fetoprotein (AFP) with and without nuchal translucency. Singleton pregnancies recruited at 11-14weeks and followed until delivery. The four maternal markers were measured using Kryptor (ThermoFisher-BRAHMS) and adjusted for gestational age and maternal characteristics. The risk of Down syndrome was calculated using the Fetal Medicine Foundation algorithm and multivariate linear regression analyses in all cases and in 2,200 controls. Receiver-operator characteristic (ROC) curves were used to calculate the detection and false-positive rates. Twenty-six (0.2%) cases of Down syndrome were diagnosed among 13,386 participants. The combination of the four biomarkers could have detected 88% (95% CI: 72-97%) of the cases at a false-positive rate of 13% (95% CI: 12-15%). The addition of nuchal translucency would have increased the detection rate to 96% (95% CI: 82-99%) at a false-positive rate of 4% (95% CI: 4-5%) using a 1:300 cut-off and to 100% (95% CI: 89-100%) at a false-positive rate of 6% (95% CI: 5-8%) using a 1:500 cut-off. First-trimester screening using biochemical markers allows the identification of approximately 88% of Down syndrome cases for a false-positive rate of 13%. The addition of nuchal translucency raises the detection rate above 95% with a false-positive rate below 5%.

First-Trimester Screening for HELLP Syndrome-Prediction Model Based on MicroRNA Biomarkers and Maternal Clinical Characteristics.

We evaluated the potential of cardiovascular-disease-associated microRNAs for early prediction of HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome. Gene expression profiling of 29 microRNAs was performed on whole peripheral venous blood samples collected between 10 and 13 weeks of gestation using real-time RT-PCR. The retrospective study involved singleton pregnancies of Caucasian descent only diagnosed with HELLP syndrome (n = 14) and 80 normal-term pregnancies. Upregulation of six microRNAs (miR-1-3p, miR-17-5p, miR-143-3p, miR-146a-5p, miR-181a-5p, and miR-499a-5p) was observed in pregnancies destined to develop HELLP syndrome. The combination of all six microRNAs showed a relatively high accuracy for the early identification of pregnancies destined to develop HELLP syndrome (AUC 0.903, p < 0.001, 78.57% sensitivity, 93.75% specificity, cut-off > 0.1622). It revealed 78.57% of HELLP pregnancies at a 10.0% false-positive rate (FPR). The predictive model for HELLP syndrome based on whole peripheral venous blood microRNA biomarkers was further extended to maternal clinical characteristics, most of which were identified as risk factors for the development of HELLP syndrome (maternal age and BMI values at early stages of gestation, the presence of any kind of autoimmune disease, the necessity to undergo an infertility treatment by assisted reproductive technology, a history of HELLP syndrome and/or pre-eclampsia in a previous gestation, and the presence of trombophilic gene mutations). Then, 85.71% of cases were identified at a 10.0% FPR. When another clinical variable (the positivity of the first-trimester screening for pre-eclampsia and/or fetal growth restriction by the Fetal Medicine Foundation algorithm) was implemented in the HELLP prediction model, the predictive power was increased further to 92.86% at a 10.0% FPR. The model based on the combination of selected cardiovascular-disease-associated microRNAs and maternal clinical characteristics has a very high predictive potential for HELLP syndrome and may be implemented in routine first-trimester screening programs.

A Comparison of Changes in the Mean Arterial Blood Pressure and Mean Uterine Artery Pulsatility Index from 11-14 to 19-24 + 6 Gestation Weeks in Low-Risk and High-Risk Asian Indian Pregnant Women.

Aim The aim of this study was to determine the changes in the mean arterial blood pressure (MAP) and mean uterine artery (UtA) pulsatility index (PI) from 11-14 to 19-24 + 6 gestation weeks in Asian Indian pregnant women. Methods Clinical and demographic details, MAP, and mean UtA PI measures were ascertained for pregnant women at 11 to 14 gestation weeks and 19-24 + 6 gestation weeks. Women were categorized as a high-or-low risk for preterm preeclampsia using the Fetal Medicine Foundation algorithm and 1 in 150 cutoff. High-risk pregnant women were recommended low-dose aspirin 150 mg daily at bedtime. Changes in MAP and mean UtA PI were compared for gestational age intervals and high-and-low risk women using nonparametric tests. Results The study analyzed the results of 1,163 pregnant women. Both MAP (mean difference: 5.14, p < 0.001) and mean UtA PI (mean difference: 0.14, p < 0.001) remained significantly higher at the second-trimester assessment in high-risk pregnant women compared to low-risk pregnant women. Seventy-seven (35.16%) of the 219 pregnant women with abnormal mean UtA PI in the first trimester had an abnormal mean UtA PI in the second-trimester assessment. One hundred (10.59%) of the 944 pregnant women with normal mean UtA PI in the first trimester had an abnormal mean UtA PI in the 19-24 + 6 weeks assessment. Seventy-seven pregnant women (6.62% of 1,163 women, 95% confidence interval: 5.33, 8.20) had an abnormal mean UtA PI at both gestation age intervals. High-risk pregnant women taking low-dose aspirin daily showed a larger reduction in mean UtA PI compared to high-risk pregnant women that did not report the use of low-dose aspirin (0.89 vs. 0.62, p <0.001) Conclusion MAP and mean UtA PI decreased significantly from the first to the second trimester of pregnancy. Sequential assessment of the MAP and mean UtA PI in the first and second trimesters of pregnancy will be useful for fetal radiologists in India to identify a subgroup of women with abnormal mean UtA PI at both trimesters that may need more intense surveillance and follow-up till childbirth.

First trimester screening and prediction of preeclampsia by Application of Fetal Medicine Foundation Algorithm at Tanta University

Background: Preeclampsia (PE) is a complex illness linked to conception that affects a variety of bodily functions and is usually connected with perinatal morbidity and deaths. Early PE anticipation will reduce this linked morbidity and death by allowing for routine maternal and foetal monitoring and the use of preventative measures. Aim of the work: the goal of this study is to investigate whether the measurement of maternal serum placental growth factor (PlGF) combined with uterine artery Doppler ultrasound, are useful in early predicting PE and to examine the diagnostic accuracy of the Fetal Medicine Foundation (FMF) Algorithm for the early screening and anticipation of the high- risk PE at 11-13 weeks conception in a group of pregnant women. Patients and Methods: one hundred and twenty primigravida women with living, singleton fetus at 11-13 weeks conception without risk factors other than being primigravida attending antenatal care clinic at the Department of Obstetrics and Gynecology at Tanta University Hospitals. All cases were subjected to ; A signed informed written consent, proper history taking, full clinical examination, estimation of body mass index (BMI), blood pressures and determination of mean arterial blood pressure (MAP), ultrasound, Uterine artery doppler ultrasound examination with the determination of the mean Pulsatility index (PI) of the uterine arteries. Maternal serum levels of PlGF were also measured by specific immunoassay (ELISA). The measured values of MAP, mean uterine artery pulsatility index (PI) and PlGF were converted into multiples of the median (MoM). Then the FMF model was used for the determination of patient-specific risk of PE at 11-13 weeks conception in each case. Results: The main results of the present study revealed that; Only 11 of 120 normal pregnant women were categorized as a high PE risk with a percentage of 9.2% and the rest 109 cases were low PE risk with a percentage of 90.8% by application of FMF algorithm. There was a significant difference between the high and low risks regarding the mean uterian UtA-Pi and PIGF levels at 11–13 weeks. Receiver operating characteristic curve (ROC) demonstrate to what extent it can be depended on PlGF, mean UtA-PI and MAP as a predictor for PE denoting the significant diagnostic performance for PIGF and mean uterine artery pulsatility index (PI). The optimal cutoff value of PlGF value using the ROC curve was ≤40 leading to a sensitivity of 90.91%, a specificity of 96.33%, a PPV of 71.4, a NPV of 99.1% and an accuracy of 95.83%. While the optimal cutoff measure of mean uterine artery PI value using the ROC curve was >1.91 leading to a sensitivity of 90.91%, a specificity of 96.33%, PPV of 71.4, NPV of 99.1% and an accuracy of 95.83%. Conclusion: On the basis of these results, it could be concluded that the combined measurement of maternal serum PlGF concentrations and mean PI of the uterine arteries at 11–13 weeks of conception may help to predict the high-risk PE in primigravida when other parameters of PE anticipation are normal. And The FMF screening algorithm for the high-risk PE group performing satisfactorily. PE estimated by the competing risk model incorporated in the FMF algorithm may be applicable locally, and the earlier screening in conception would allow women at a higher risk to be monitored accordingly, participate in early intervention trials, and commence prophylactic therapy.

The Implementation of Preeclampsia Screening and Prevention (IMPRESS) Study

Preeclampsia affects between 2% and 5% of pregnancies and is one of the leading causes of perinatal morbidity and mortality worldwide. Despite strong evidence that the combination of systematic preeclampsia screening based on the Fetal Medicine Foundation preeclampsia risk calculation algorithm with treatment of high-risk patients with low-dose aspirin reduces the incidence of preterm preeclampsia more than currently used risk-factor-based screening, real-world implementation studies have not yet been done in Canada. This study aimed to assess the operational feasibility of implementing first-trimester screening and prevention of preterm preeclampsia (<37 weeks) alongside a publicly funded first-trimester combined screening program for aneuploidies. This was a prospective implementation study. Consecutive pregnant patients referred for first-trimester combined screening (11-13+6 weeks) were offered screening for preeclampsia based on the Fetal Medicine Foundation algorithm concomitantly with their aneuploidy screen. Consenting participants were screened using maternal risk factors, mean arterial pressure, uterine artery Doppler pulsatility index, pregnancy-associated plasma protein-A, and placental growth factor. Risk for preterm preeclampsia (<37 weeks) was calculated using the Fetal Medicine Foundation algorithm, and individuals with a risk score ≥1 per 100 were recommended to use aspirin (162 mg once daily at bedtime, <16-36 weeks). Implementation metrics assessed included: acceptability, operational impact, proportion of aspirin initiation, quality and safety measures, and screen performance. Between December 1, 2020 and April 23, 2021, 1124 patients consented to preeclampsia screening (98.3% uptake), and 92 (8.2%) screened positive. Appointments for patients receiving first-trimester combined screening aneuploidy and preeclampsia screening averaged 6 minutes longer than first-trimester combined screening alone, and adding uterine artery Doppler pulsatility index averaged 2 minutes. Of the 92 patients who screened as high-risk for preeclampsia, 72 (78.3%) were successfully contacted before 16 weeks' gestation. Of these, 62 (86.1%) initiated aspirin, and 10 (13.9%) did not. Performance audit identified a consistent negative bias with mean arterial pressure measurements (median multiple of the median <1 in 10%); other variables were satisfactory. There were 7 cases of preterm preeclampsia (0.69%): 5 and 2 in the high- and low-risk groups, respectively. Screening detected 5 of 7 (71.4 %) preterm preeclampsia cases, with improved performance after adjustment for aspirin treatment effect. This study confirms the operational feasibility of implementing an evidence-based preeclampsia screening and prevention program in a publicly funded Canadian setting. This will facilitate implementation into clinical service and the scaling up of this program at a regional and provincial level.

Novel First-Trimester Prediction Model for Any Type of Preterm Birth Occurring before 37 Gestational Weeks in the Absence of Other Pregnancy-Related Complications Based on Cardiovascular Disease-Associated MicroRNAs and Basic Maternal Clinical Characteristics.

The goal of the study was to establish an efficient first-trimester predictive model for any type of preterm birth before 37 gestational weeks (spontaneous preterm birth (PTB) or preterm prelabor rupture of membranes (PPROM)) in the absence of other pregnancy-related complications, such as gestational hypertension, preeclampsia, fetal growth restriction, or small for gestational age. The retrospective study was performed in the period from 11/2012 to 3/2020. Peripheral blood samples were collected from 6440 Caucasian individuals involving 41 PTB and 65 PPROM singleton pregnancies. A control group with 80 singleton term pregnancies was selected on the basis of equal sample-storage time. A combination of only six microRNAs (miR-16-5p, miR-21-5p, miR-24-3p, miR-133a-3p, miR-155-5p, and miR-210-3p; AUC 0.812, p < 0.001, 70.75% sensitivity, 78.75% specificity, cut-off > 0.652) could predict preterm delivery before 37 gestational weeks in early stages of gestation in 52.83% of pregnancies with a 10.0% FPR. This predictive model for preterm birth based on aberrant microRNA expression profile was further improved via implementation of maternal clinical characteristics (maternal age and BMI at early stages of gestation, infertility treatment with assisted reproductive technology, occurrence of preterm delivery before 37 gestational weeks in previous pregnancy(ies), and presence of any kind of autoimmune disease (rheumatoid arthritis, systemic lupus erythematosus, antiphospholipid syndrome, type 1 diabetes mellitus, or other autoimmune disease)). With this model, 69.81% of pregnancies destined to deliver before 37 gestational weeks were identified with a 10.0% FPR at early stages of gestation. When other clinical variables as well as those mentioned above—such as positive first-trimester screening for early preeclampsia with onset before 34 gestational weeks and/or fetal growth restriction with onset before 37 gestational weeks using the Fetal Medicine Foundation algorithm, as well as positive first-trimester screening for spontaneous preterm birth with onset before 34 gestational weeks using the Fetal Medicine Foundation algorithm—were added to the predictive model for preterm birth, the predictive power was even slightly increased to 71.70% with a 10.0% FPR. Nevertheless, we prefer to keep the first-trimester screening for any type of preterm birth occurring before 37 gestational weeks in the absence of other pregnancy-related complications as simple as possible.

Cardiovascular Disease-Associated MicroRNAs as Novel Biomarkers of First-Trimester Screening for Gestational Diabetes Mellitus in the Absence of Other Pregnancy-Related Complications

We assessed the diagnostic potential of cardiovascular disease-associated microRNAs for the early prediction of gestational diabetes mellitus (GDM) in singleton pregnancies of Caucasian descent in the absence of other pregnancy-related complications. Whole peripheral venous blood samples were collected within 10 to 13 weeks of gestation. This retrospective study involved all pregnancies diagnosed with only GDM (n = 121) and 80 normal term pregnancies selected with regard to equality of sample storage time. Gene expression of 29 microRNAs was assessed using real-time RT-PCR. Upregulation of 11 microRNAs (miR-1-3p, miR-20a-5p, miR-20b-5p, miR-23a-3p, miR-100-5p, miR-125b-5p, miR-126-3p, miR-181a-5p, miR-195-5p, miR-499a-5p, and miR-574-3p) was observed in pregnancies destinated to develop GDM. Combined screening of all 11 dysregulated microRNAs showed the highest accuracy for the early identification of pregnancies destinated to develop GDM. This screening identified 47.93% of GDM pregnancies at a 10.0% false positive rate (FPR). The predictive model for GDM based on aberrant microRNA expression profile was further improved via the implementation of clinical characteristics (maternal age and BMI at early stages of gestation and an infertility treatment by assisted reproductive technology). Following this, 69.17% of GDM pregnancies were identified at a 10.0% FPR. The effective prediction model specifically for severe GDM requiring administration of therapy involved using a combination of these three clinical characteristics and three microRNA biomarkers (miR-20a-5p, miR-20b-5p, and miR-195-5p). This model identified 78.95% of cases at a 10.0% FPR. The effective prediction model for GDM managed by diet only required the involvement of these three clinical characteristics and eight microRNA biomarkers (miR-1-3p, miR-20a-5p, miR-20b-5p, miR-100-5p, miR-125b-5p, miR-195-5p, miR-499a-5p, and miR-574-3p). With this, the model identified 50.50% of GDM pregnancies managed by diet only at a 10.0% FPR. When other clinical variables such as history of miscarriage, the presence of trombophilic gene mutations, positive first-trimester screening for preeclampsia and/or fetal growth restriction by the Fetal Medicine Foundation algorithm, and family history of diabetes mellitus in first-degree relatives were included in the GDM prediction model, the predictive power was further increased at a 10.0% FPR (72.50% GDM in total, 89.47% GDM requiring therapy, and 56.44% GDM managed by diet only). Cardiovascular disease-associated microRNAs represent promising early biomarkers to be implemented into routine first-trimester screening programs with a very good predictive potential for GDM.

First-trimester screening for pre-eclampsia and small for gestational age: A comparison of the gaussian and Fetal Medicine Foundation algorithms.

Pre-eclampsia (PE) and small for gestational age (SGA) can be predicted from the first trimester. The most widely used algorithm worldwide is the Fetal Medicine Foundation (FMF) algorithm. The recently described Gaussian algorithm has reported excellent results although it is unlikely to be externally validated. Therefore, as an alternative approach, we compared the predictive accuracy for PE and SGA of the Gaussian and FMF algorithms. Secondary analysis of a prospective cohort study was conducted at Vall d'Hebron University Hospital (Barcelona) with 2641 singleton pregnancies. The areas under the curve for the predictive performance for early-onset and preterm PE and early-onset and preterm SGA were calculated with the Gaussian and FMF algorithms and subsequently compared. The FMF and Gaussian algorithms showed a similar predictive performance for most outcomes and marker combinations. Nevertheless, significant differences for early-onset PE prediction favored the Gaussian algorithm in the following combinations: mean arterial blood pressure (MAP) with pregnancy-associated plasma protein A, MAP with placental growth factor, and MAP alone. The first-trimester Gaussian and FMF algorithms have similar performances for PE and SGA prediction when applied with all markers within a routine care setting in a Spanish population, adding evidence to the external validity of the FMF algorithm.

Routine first-trimester pre-eclampsia screening and risk of preterm birth.

ObjectivesPreterm birth (PTB) is a major public health problem worldwide. It can occur spontaneously or be medically indicated for obstetric complications, such as pre‐eclampsia (PE) or fetal growth restriction. The main objective of this study was to investigate whether there is a shared uteroplacental etiology in the first trimester of pregnancy across PTB subtypes.MethodsThis was a retrospective cohort study of singleton pregnancies that underwent screening for preterm PE as part of their routine first‐trimester ultrasound assessment at a tertiary center in London, UK, between March 2018 and December 2020. Screening for preterm PE was performed using the Fetal Medicine Foundation algorithm, which includes maternal factors, mean arterial pressure (MAP), uterine artery pulsatility index (UtA‐PI) and pregnancy‐associated plasma protein‐A (PAPP‐A). Women with a risk of ≥ 1 in 50 for preterm PE were classified as high risk and offered prophylactic aspirin (150 mg once a day) and serial ultrasound assessments. The following delivery outcomes were evaluated: PTB < 37 weeks, iatrogenic PTB (iPTB) and spontaneous PTB (sPTB). Logistic regression analyses were performed to assess the association of PTB, iPTB and sPTB with an increased risk of preterm PE. A model for prediction of PTB < 37 weeks and < 33 weeks was developed and its performance was compared with that of an existing model in the literature.ResultsA total of 11 437 women were included in the study, of whom 475 (4.2%) had PTB. Of these, 308 (64.8%) were sPTB and 167 (35.2%) were iPTB. Patients with PTB had a higher body mass index, were more likely to be of black or Asian ethnicity, be smokers, have pregestational hypertension or diabetes, or have a history of previous PTB. They also had higher MAP (87.7 vs 86.0 mmHg, P < 0.0001), higher UtA‐PI multiples of the median (MoM) (0.99 vs 0.92, P < 0.0001) and lower PAPP‐A MoM (0.89 vs 1.08, P < 0.0001) compared to women with a term birth. In women at high risk of PE, the odds ratio for iPTB was 6.0 (95% CI, 4.29–8.43; P < 0.0001) and that for sPTB was 2.0 (95% CI, 1.46–2.86; P < 0.0001). A prediction model for PTB < 37 weeks and < 33 weeks, developed based on this cohort, included previous PTB, black ethnicity, chronic hypertension, diabetes mellitus, PAPP‐A MoM and UtA‐PI MoM. The performance of the model was similar to that of an existing first‐trimester prediction model for PTB < 33 weeks (area under the curve, 0.704 (95% CI, 0.653–0.754) vs 0.694 (95% CI, 0.643–0.746)).ConclusionsIncreased first‐trimester risk for uteroplacental dysfunction was associated with both iPTB and sPTB, implying a shared etiological pathway. The same factors used to predict PE risk show acceptable discrimination to predict PTB at < 33 weeks. Women at high risk of uteroplacental dysfunction may warrant additional monitoring and management for an increased risk of sPTB. © 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Routine first trimester combined screening for preterm preeclampsia in Australia: A multicenter clinical implementation cohort study.

To assess pregnancy outcomes following first trimester combined screening for preterm preeclampsia in Australia. We compared pregnancy outcomes of women with singleton pregnancies who underwent first trimester combined preeclampsia screening with the Fetal Medicine Foundation algorithm between 2014 and 2017 in Melbourne and Sydney, Australia, with those from women who received standard care. The primary outcomes were preterm preeclampsia and screening performance. Effect estimates were presented as risk ratios with 95% confidence intervals. A total of 29618 women underwent combined screening and 301566 women received standard care. Women who had combined screening were less likely to have preeclampsia, preterm birth, small neonates, and low Apgar scores than the general population. Women with high-risk results (≥1 in 100) were more likely to develop preterm preeclampsia (2.1% vs. 0.7%, risk ratio [RR] 3.04, 95% CI 2.46-3.77), while low-risk women (risk <1 in 100) had lower rates of preterm preeclampsia (0.2% vs. 0.7%, RR 0.26, 95% CI 0.19-0.35) and other pregnancy complications. Screening detected 65.2% (95% CI 56.4-73.2%) of all preterm preeclampsia cases, with improved performance after adjustment for treatment effect. First trimester screening for preeclampsia in clinical practice identified a population at high risk of adverse pregnancy outcomes and low-risk women who may be suitable for less intensive antenatal care.

Performance of Fetal Medicine Foundation algorithm for first trimester preeclampsia screening in an indigenous south Asian population

BackgroundTo evaluate the performance of the Fetal Medicine Foundation (FMF) preterm preeclampsia (PE) screening algorithm in an indigenous South Asian population.MethodsThis was a prospective observational cohort study conducted in a tertiary maternal fetal unit in Delhi, India over 2 years. The study population comprised of 1863 women carrying a singleton pregnancy and of South Asian ethnicity who were screened for preterm pre-eclampsia (PE) between 11 and 14 weeks of gestation using Mean Arterial Pressure (MAP), transvaginal Mean Uterine Artery Pulsatility Index (UtAPI) and biochemical markers - Pregnancy Associated Plasma Protein-A (PAPP-A) and Placental Growth Factor.. Absolutemeasurements of noted biomarkers were converted to multiples of the expected gestational median (MoMS) which were then used to estimate risk for preterm PE < 37 weeks using Astraia software. Women with preterm PE risk of ≥1:100 was classified as as high risk. Detection rates (DR) at 10% false positive rate were calculated after adjusting for prophylactic aspirin use (either 75 or 150 mg).ResultsThe incidence of PE and preterm PE were 3.17% (59/1863) and 1.34% (25/1863) respectively. PAPP-A and PlGF MoM distribution medians were 0.86 and 0.87 MoM and significantly deviated from 1 MoM. 431 (23.1%) women had a risk of ≥1:100, 75 (17.8%) of who received aspirin. Unadjusted DR using ≥1:100 threshold was 76%.Estimated DRs for a fixed 10% FPR ranged from 52.5 to 80% depending on biomarker combination after recentering MoMs and adjusting for aspirin use.ConclusionThe FMF algorithm whilst performing satisfactorily could still be further improved to ensure that biophysical and biochemical markers are correctly adjusted for indigenous South Asian women.

Prospective evaluation of first-trimester screening strategy for preterm pre-eclampsia and its clinical applicability in China.

To evaluate, in a Chinese population, the performance of a screening strategy for preterm pre-eclampsia (PE) using The Fetal Medicine Foundation (FMF)'s competing-risks model and to explore its clinical applicability in mainland China. This was a prospective, multicenter, observational cohort study including 10 899 women with singleton pregnancy who sought prenatal care at one of 13 hospitals, located in seven cities in mainland China, between 1 December 2017 and 30 December 2019. Mean arterial pressure (MAP), uterine artery pulsatility index (UtA-PI) and maternal serum levels of placental growth factor (PlGF) and pregnancy-associated plasma protein-A (PAPP-A) at 11 + 0 to 13 + 6 weeks' gestation were measured and converted into multiples of the median using Chinese reference ranges. Individualized risk for preterm PE was calculated using the FMF algorithm. Prior risk was calculated based on maternal demographic characteristics and obstetric history. We evaluated the efficiency of the screening strategy using various combinations of biomarkers and analyzed its predictive performance for a composite of placenta-associated adverse pregnancy outcomes, including PE, placental abruption, small-for-gestational age (SGA) and preterm birth, at fixed false-positive rates for preterm PE. We identified 312 pregnancies that developed PE, of which 117 cases were diagnosed as preterm PE (< 37 weeks' gestation). There were 386 pregnancies complicated by severe composite placenta-associated adverse outcome, including preterm PE, 146 cases of severe SGA (birth weight < 3rd percentile) neonate, 61 cases with placental abruption and 109 cases of early preterm birth < 34 gestational weeks. The triple-marker model containing biomarkers MAP, UtA-PI and PAPP-A achieved, at fixed false-positive rates of 10%, 15% and 20%, detection rates for preterm PE of 65.0%, 72.7% and 76.1%, respectively, and detection rates for severe composite placenta-associated adverse outcome of 34.7%, 41.7% and 46.4%, respectively. Replacing PAPP-A with PlGF or adding PlGF to the model did not improve the performance. Of women screening positive for preterm PE at a fixed 5% false-positive rate, an estimated 30% developed at least one placenta-associated adverse pregnancy outcome, including PE, placental abruption, SGA (birth weight < 10th percentile) and preterm birth < 37 weeks. The FMF competing-risks model for preterm PE was found to be effective in screening a mainland Chinese population. Women who screened positive for preterm PE had increased risk for other placenta-associated pregnancy complications. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

ASPRE trial: risk factors for development of preterm pre-eclampsia despite aspirin prophylaxis.

To examine the possible risk factors amongst maternal characteristics, medical and obstetric history, pre-eclampsia (PE)-specific biomarkers and estimated-risk group, according to The Fetal Medicine Foundation (FMF) algorithm, that are associated with the development of preterm PE with delivery at < 37 weeks' gestation despite aspirin prophylaxis. This was a secondary analysis of data from the ASPRE trial. The study population consisted of women with singleton pregnancy who were deemed to be at high risk for preterm PE, based on the FMF algorithm that combines maternal factors, mean arterial pressure, uterine artery pulsatility index, serum pregnancy-associated plasma protein-A and placental growth factor (PlGF) at 11-13 weeks' gestation. High-risk women were randomized to receive aspirin (150 mg/day) vs placebo from 11-14 until 36 weeks' gestation. The primary outcome was PE with delivery at < 37 weeks' gestation (preterm PE). Multivariate logistic regression analysis was performed to identify independent predictors of preterm PE after adjusting for the use of aspirin and other covariates. Among 1592 high-risk women, the incidence of preterm PE was 3.0% (n = 48). The interaction between aspirin usage and history of chronic hypertension was significant in the prediction of preterm PE (P = 0.042), which indicated that there was no treatment effect in high-risk women who had chronic hypertension compared with those who did not. Adjusting for aspirin use, the interaction between aspirin and chronic hypertension and other covariates, independent predictors for the development of preterm PE were PlGF multiples of the median (MoM) (adjusted odds ratio (aOR), 0.226 (95% CI, 0.070-0.723)) and estimated-risk group based on the FMF algorithm. Compared to women with an estimated risk of 1 in 51 to 1 in 100, those with an estimated risk of 1 in 2 to 1 in 10 had a 7-fold higher risk of developing preterm PE (aOR, 6.706 (95% CI, 2.381-18.883)), and those with an estimated risk of 1 in 11 to 1 in 50 had a 3-fold higher risk of preterm PE (aOR, 2.769 (95% CI, 1.105-6.939)). PlGF MoM was an independent predictor for preterm PE among women with an estimated risk of 1 in 2 to 1 in 10 (aOR, 0.055 (95% CI, 0.005-0.668)). Among women with an estimated risk of 1 in 11 to 1 in 100, the use of aspirin was an independent predictor of preterm PE (aOR, 0.276 (95% CI, 0.111-0.689)). The cut-off for PlGF with the best performance for the prediction of preterm PE was 0.712 MoM, with an aOR of 3.677 (95% CI, 1.526-8.862). In pregnancies at high risk of preterm PE identified by screening at 11-13 weeks' gestation using the FMF algorithm, a very high-risk result (estimated risk ≥ 1 in 50), compared to an estimated risk of 1 in 51 to 1 in 100, chronic hypertension, compared to no chronic hypertension, and low PlGF concentration (< 0.712 MoM), compared to PlGF ≥ 0.712 MoM, were associated with the development of preterm PE despite aspirin prophylaxis. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Clinical implementation of pre-eclampsia screening in the first trimester of pregnancy.

Early identification of preeclampia in the first trimester of pregnancy represents one of the major challenges of modern fetal medicine. The primary aim of our study was to evaluate the effectiveness of implementation of preeclampsia screening in Tuscany, Italy. The secondary aim was to evaluate pregnancy/neonatal outcome in the positive screening group compared with the negative screening group. Retrospective study including singleton pregnancies undergoing screening for preeclampsia. The screening test was a multiparametric algorithm based on maternal history, biochemical and biophysical parameters (Fetal Medicine Foundation algorithm). The overall performance of the test was calculated, in terms of sensitivity, specificity, positive and negative predictive value and in relation to gestational age at onset (primary aim). Pregnancy and neonatal outcomes were then compared between the positive and negative population at preeclampsia screening test (secondary aim). Of the 5719 patients enrolled, 4797 were included in the analysis. The sensitivity for early onset of preeclampsia (≤34weeks) was 0.75 (CI:0.41-0.93) and specificity 0.93 (CI:0.92-0.94) for a false positive rate of 7%. The population that tested positive for preeclampsia screening showed a higher incidence of deliveries at lower gestational ages (p<0.001), preeclampsia onset despite prophylaxis with aspirin (p<0.001), emergency caesarean section (p<0.001), low fetal birth weight (p<0.001) and neonatal admission in intensive care unit (p<0.001). Our data confirm the validity of first trimester screening test in identifying a category of patients at greatest risk for preeclampsia even in the presence of a post-test pharmacological prophylaxis.