Mid-trimester uterine artery Doppler for aspirin discontinuation in pregnancies at high risk for preterm pre-eclampsia: Post-hoc analysis of StopPRE trial.

OBJECTIVE: To assess whether aspirin treatment can be discontinued in pregnancies with normal uterine artery pulsatility index (≤90th percentile) at 24-28 weeks. DESIGN: Post-hoc analysis of a clinical trial. SETTING: Nine maternity hospitals in Spain. POPULATION OR SAMPLE: Pregnant individuals at high risk of pre-eclampsia at 11-13 weeks and normal uterine artery Doppler at 24-28 weeks. METHODS: All participants received treatment with daily aspirin at a dose of 150 mg. Participants were randomly assigned, in a 1:1 ratio, either to continue aspirin treatment until 36 weeks (control group) or to discontinue aspirin treatment (intervention group), between September 2019 and September 2021. In this secondary analysis, women with a UtAPI >90th percentile at 24-28 weeks were excluded. The non-inferiority margin was set at a difference of 1.9% for the incidence of preterm pre-eclampsia. MAIN OUTCOME MEASURES: Incidence of preterm pre-eclampsia. RESULTS: Of the 1611 eligible women, 139 were excluded for UtAPI >90th percentile or if UtAPI was not available. Finally, 804 were included in this post-hoc analysis. Preterm pre-eclampsia occurred in three of 409 (0.7%) women in the aspirin discontinuation group and five of 395 (1.3%) women in the continuation group (-0.53; 95% CI -1.91 to 0.85), indicating non-inferiority of aspirin discontinuation. CONCLUSIONS: Discontinuing aspirin treatment at 24-28 weeks in women with a UtAPI ≤90th percentile was non-inferior to continuing aspirin treatment until 36 weeks for preventing preterm pre-eclampsia.

Clinical effectiveness of routine first-trimester combined screening for pre-eclampsia in Spain with the addition of placental growth factor.

INTRODUCTION: Pre-eclampsia affects 2%-8% of pregnancies and is one of the leading causes of maternal and perinatal morbidity and mortality. First-trimester screening using an algorithm that combines maternal characteristics, mean arterial blood pressure, uterine artery pulsatility index and biomarkers (pregnancy-associated plasma protein-A and placental growth factor) is the method that achieves a greater diagnostic accuracy. It has been shown that daily salicylic acid administration before 16 weeks in women at a high risk for pre-eclampsia can reduce the incidence of preterm pre-eclampsia. However, no previous studies have evaluated the impact of routine first-trimester combined screening for pre-eclampsia with placental growth factor after being implemented in the clinical practice. MATERIAL AND METHODS: This was a multicenter cohort study conducted in eight different maternities across Spain. Participants in the reference group were prospectively recruited between October 2015 and September 2017. Participants in the study group were retrospectively recruited between March 2019 and May 2021. Pre-eclampsia risk was calculated between 11+0 and 13+6 weeks using the Gaussian algorithm combining maternal characteristics, mean arterial pressure, uterine arteries pulsatility index, pregnancy-associated plasma protein-A and placental growth factor. Patients with a risk greater than 1/170 were prescribed daily salicylic acid 150 mg until 36 weeks. Patients in the reference group did not receive salicylic acid during gestation. RESULTS: A significant reduction was observed in preterm pre-eclampsia (OR 0.47; 95% CI: 0.30-0.73), early-onset (<34 weeks) pre-eclampsia (OR 0.35; 95% CI: 0.16-0.77), preterm small for gestational age newborn (OR 0.57; 95% CI: 0.40-0.82), spontaneous preterm birth (OR 0.72; 95% CI: 0.57-0.90), and admission to intensive care unit (OR 0.55; 95% CI: 0.37-0.81). A greater treatment adherence resulted in a significant reduction in adverse outcomes. CONCLUSIONS: Routine first-trimester screening for pre-eclampsia with placental growth factor leads to a reduction in preterm pre-eclampsia and other pregnancy complications. Aspirin treatment compliance has a great impact on the effectiveness of this screening program.

Aspirin Discontinuation at 24 to 28 Weeks' Gestation in Pregnancies at High Risk of Preterm Preeclampsia: A Randomized Clinical Trial.

Importance: Aspirin reduces the incidence of preterm preeclampsia by 62% in pregnant individuals at high risk of preeclampsia. However, aspirin might be associated with an increased risk of peripartum bleeding, which could be mitigated by discontinuing aspirin before term (37 weeks of gestation) and by an accurate selection of individuals at higher risk of preeclampsia in the first trimester of pregnancy. Objective: To determine whether aspirin discontinuation in pregnant individuals with normal soluble fms-like tyrosine kinase-1 to placental growth factor (sFlt-1:PlGF) ratio between 24 and 28 weeks of gestation was noninferior to aspirin continuation to prevent preterm preeclampsia. Design, Setting, and Participants: Multicenter, open-label, randomized, phase 3, noninferiority trial conducted in 9 maternity hospitals across Spain. Pregnant individuals (n = 968) at high risk of preeclampsia during the first-trimester screening and an sFlt-1:PlGF ratio of 38 or less at 24 to 28 weeks of gestation were recruited between August 20, 2019, and September 15, 2021; of those, 936 were analyzed (intervention: n = 473; control: n = 463). Follow-up was until delivery for all participants. Interventions: Enrolled patients were randomly assigned in a 1:1 ratio to aspirin discontinuation (intervention group) or aspirin continuation until 36 weeks of gestation (control group). Main Outcomes and Measures: Noninferiority was met if the higher 95% CI for the difference in preterm preeclampsia incidences between groups was less than 1.9%. Results: Among the 936 participants, the mean (SD) age was 32.4 (5.8) years; 3.4% were Black and 93% were White. The incidence of preterm preeclampsia was 1.48% (7/473) in the intervention group and 1.73% (8/463) in the control group (absolute difference, -0.25% [95% CI, -1.86% to 1.36%]), indicating noninferiority. Conclusions and Relevance: Aspirin discontinuation at 24 to 28 weeks of gestation was noninferior to aspirin continuation for preventing preterm preeclampsia in pregnant individuals at high risk of preeclampsia and a normal sFlt-1:PlGF ratio. Trial Registration: ClinicalTrials.gov Identifier: NCT03741179 and ClinicalTrialsRegister.eu Identifier: 2018-000811-26.

Usefulness of angiogenic factors in prenatal counseling of late-onset fetal growth-restricted and small-for-gestational-age gestations: a prospective observational study.

OBJECTIVES: To create a predictive model including biomarkers and evaluate its ability to predict adverse perinatal outcomes in late-onset small fetuses, ultimately helping to provide individualized counseling at the time of diagnosis. METHODS: This was a prospective observational study, including singleton pregnancies with an estimated fetal weight (EFW) below the 10th percentile, at a gestational age between 32 + 0 and 36 + 6 weeks of gestation (WG). Variables recorded at diagnosis to predict adverse pregnancy outcomes were: soluble fms-like tyrosine-kinase-1 to placental growth factor ratio (sFlt-1/PlGF), fetal Doppler (umbilical artery and middle cerebral artery), uterine artery pulsatility index (UtAPI), EFW percentile, gestational age, and the presence of maternal risk factors for placental insufficiency. Logistic regression models were developed for the prediction of three co-primary outcomes: composite adverse perinatal outcomes (APO), and the need for elective delivery before 35 or 37 WG. RESULTS: Sixty (52.2%) fetal growth restricted (FGR) and 55 (47.8%) small for gestational age (SGA) were enrolled. Thirteen (11.3%) women needed elective delivery before 35 WG and 27 (23.5%) women before 37 WG. At least one APO occurred in 43 (37.4%) pregnancies. The best marker in univariate analyses was the sFlt-1/PlGF ratio [AUC = 0.932 (95% CI, 0.864-0.999)]. The multivariate model including sFlt-1/PlGF showed a better predictive performance for APO than the multivariate model without sFlt-1/PlGF (P < 0.024). CONCLUSIONS: sFlt-1/PlGF is a good predictor of APO at the time of late-onset FGR/SGA diagnosis. Our predictive models may be useful to provide early individualized prenatal counseling in this group of women. Further studies are needed to validate these preliminary findings in a larger cohort.

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

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Confirmation of preeclampsia-like syndrome induced by severe COVID-19: an observational study.

BACKGROUND: Since the outbreak of the COVID-19 pandemic, some studies have reported an increased preeclampsia incidence in pregnant women with SARS-CoV-2 infection. Several explanations for this association have been proposed, including a preeclampsia-like syndrome induced by severe COVID-19. This syndrome was described in a small case series and has not been confirmed in larger studies, and its effect on perinatal outcomes has not been studied. OBJECTIVE: This study aimed to confirm the preeclampsia-like syndrome because of COVID-19 and to investigate its implications on pregnancy outcomes and prognosis. STUDY DESIGN: This was a prospective, observational study conducted in a tertiary referral hospital. The inclusion criteria were pregnant women admitted to the intensive care unit for severe pneumonia because of COVID-19. They were classified into 3 groups based on clinical and laboratory findings: preeclampsia, preeclampsia-like syndrome, and women without preeclampsia features. The 3 cohorts were analyzed and compared at 3 different times: before, during, and after severe pneumonia. The main outcomes were incidence of adverse perinatal outcomes and signs and symptoms of PE, such as hypertension, proteinuria, thrombocytopenia, elevated liver enzymes, and increased angiogenic factors (soluble fms-like tyrosine kinase 1-to-placental growth factor ratio). RESULTS: A total of 106 women were admitted to the intensive care unit because of severe pneumonia, and 68 women were included in the study. Of those, 53 (50.0%) did not meet the diagnostic criteria for preeclampsia and remained pregnant after pneumonia (non-preeclampsia); 7 (6.6%) met the diagnostic criteria for preeclampsia, had abnormal (>38) soluble fms-like tyrosine kinase 1-to-placental growth factor ratio (preeclampsia), and delivered during severe pneumonia, and 8 (7.5%) met the diagnostic criteria for preeclampsia, had normal (≤38) soluble fms-like tyrosine kinase 1-to-placental growth factor ratio (preeclampsia like), and did not deliver during pneumonia. Despite not having delivered, most preeclampsia-related features improved after severe pneumonia in women with preeclampsia-like syndrome. Women with preeclampsia had significantly poorer outcomes than women with preeclampsia-like syndrome or without preeclampsia. CONCLUSION: More than 50% of women with severe COVID-19 and diagnostic criteria for preeclampsia may not be preeclampsia but a preeclampsia-like syndrome, which may affect up to 7.5% of women with severe COVID-19. Preeclampsia-like syndrome might have similar perinatal outcomes to those of normotensive women with severe pneumonia because of COVID-19. For these reasons, preeclampsia-like syndrome should be excluded by using soluble fms-like tyrosine kinase 1-to-placental growth factor ratio in future research and before making clinical decisions.

The Fetal Growth Restriction at Term Managed by Angiogenic Factors Versus Feto-Maternal Doppler (GRAFD) Trial to Avoid Adverse Perinatal Outcomes: Protocol for a Multicenter, Open-Label, Randomized Controlled Trial.

BACKGROUND: Fetal smallness affects 10% of pregnancies. Small fetuses are at a higher risk of adverse outcomes. Their management using estimated fetal weight and feto-maternal Doppler has a high sensitivity for adverse outcomes; however, more than 60% of fetuses are electively delivered at 37 to 38 weeks. On the other hand, classification using angiogenic factors seems to have a lower false-positive rate. Here, we present a protocol for the Fetal Growth Restriction at Term Managed by Angiogenic Factors Versus Feto-Maternal Doppler (GRAFD) trial, which compares the use of angiogenic factors and Doppler to manage small fetuses at term. OBJECTIVE: The primary objective is to demonstrate that classification based on angiogenic factors is not inferior to estimated fetal weight and Doppler at detecting fetuses at risk of adverse perinatal outcomes. METHODS: This is a multicenter, open-label, randomized controlled trial conducted in 20 hospitals across Spain. A total of 1030 singleton pregnancies with an estimated fetal weight ≤10th percentile at 36+0 to 37+6 weeks+days will be recruited and randomly allocated to either the control or the intervention group. In the control group, standard Doppler-based management will be used. In the intervention group, cases with a soluble fms-like tyrosine kinase to placental growth factor ratio ≥38 will be classified as having fetal growth restriction; otherwise, they will be classified as being small for gestational age. In both arms, the fetal growth restriction group will be delivered at ≥37 weeks and the small for gestational age group at ≥40 weeks. We will assess differences between the groups by calculating the relative risk, the absolute difference between incidences, and their 95% CIs. RESULTS: Recruitment for this study started on September 28, 2020. The study results are expected to be published in peer-reviewed journals and disseminated at international conferences in early 2023. CONCLUSIONS: The angiogenic factor-based protocol may reduce the number of pregnancies classified as having fetal growth restriction without worsening perinatal outcomes. Moreover, reducing the number of unnecessary labor inductions would reduce costs and the risks derived from possible iatrogenic complications. Additionally, fewer inductions would lower the rate of early-term neonates, thus improving neonatal outcomes and potentially reducing long-term infant morbidities. TRIAL REGISTRATION: ClinicalTrials.gov NCT04502823; https://clinicaltrials.gov/ct2/show/NCT04502823. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/37452.

sFlt-1 to PlGF ratio cut-offs to predict adverse pregnancy outcomes in early-onset FGR and SGA: a prospective observational study.

This is a prospective, observational study, conducted in a tertiary referral hospital. We enrolled 175 singleton pregnancies with estimated foetal weight below the 10th centile between 20 + 0 and 31 + 6 weeks. Placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1) and fetoplacental circulation were assessed at the time of diagnosis. Receiver operating characteristic curves were used to assess the performance of sFlt-1/PlGF for predicting adverse perinatal outcomes (APO). The optimal cut-offs to predict each adverse outcome were calculated and the resulting areas under the curve (AUC) were compared to those calculated from the cut-off points of 38, 85 and 110. The need for delivery at <30 and <34 weeks and APO were the main outcome measures. The optimal cut-off points to predict APO, delivery <30 and <34 weeks were 24.9, 116.7 and 97.5, respectively. None of them proved to be superior to 38, 85 or 110 for predicting any adverse pregnancy outcome. Impact StatementWhat is already known on this subject? Soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) are biomarkers of placental dysfunction. High sFlt-1/PlGF values predict adverse perinatal outcomes in preeclampsia (PE).What do the results of this study add? No specific thresholds have been described to identify early-onset foetal growth restriction (FGR) and small for gestational age (SGA) foetuses at higher risk of adverse outcomes. This study describes these specific cut-offs and compares their predictive capacity to those described for PE.What are the implications of these findings for clinical practice and/or further research? The sFlt-1/PlGF cut-off points of 38, 85 and 110 might be useful for ruling out the occurrence of APO and the need for elective delivery at <30 and at <34 weeks from the moment of diagnosis in early-onset FGR and SGA. These cut-offs could aid Doppler studies in the distinction between FGR and SGA.

Shared risk factors for COVID-19 and preeclampsia in the first trimester: An observational study.

INTRODUCTION: The association between preeclampsia and coronavirus disease 2019 (COVID-19) is under study. Previous publications have hypothesized the existence of shared risk factors for both conditions or a deficient trophoblastic invasion as possible explanations for this association. The primary aim of this study was to examine baseline risk factors measured in the first-trimester combined screening for preeclampsia in pregnant women with COVID-19 compared with the general population. A secondary aim of this study was to compare risk factors among patients with mild and severe COVID-19. MATERIAL AND METHODS: This was an observational retrospective study conducted at Vall d'Hebron Hospital Campus (Catalonia, Spain). Study patients were 231 pregnant women undergoing the first-trimester screening for preeclampsia and positive for severe acute respiratory syndrome coronavirus 2 between February 2020 and September 2021. The reference cohort were 13 033 women of the general population from six centers across Catalonia from May 2019 to June 2021. Based on the need for hospitalization, patients were classified in two groups: mild and severe COVID-19. First-trimester screening for preeclampsia included maternal history, mean arterial blood pressure, mean uterine artery pulsatility index (UtAPI), placental growth factor (PlGF), and pregnancy-associated plasma protein-A (PAPP-A). RESULTS: The proportion of cases at high risk for preeclampsia was significantly higher among the COVID-19 group compared with the general population (19.0% and 13.2%, respectively; p = 0.012). When analyzing risk factors for preeclampsia individually, women with COVID-19 had higher median body mass index (25.2 vs 24.5, p = 0.041), higher UtAPI multiple of the median (MoM) (1.08 vs 1.00, p < 0.001), higher incidence of chronic hypertension (2.8% vs 0.9%, p = 0.015), and there were fewer smokers (5.7% vs 11.6%, p = 0.007). The MoMs of PlGF and PAPP-A did not differ significantly between both groups (0.96 vs 0.97, p = 0.760 and 1.00 vs 1.01, p = 0.432; respectively). CONCLUSIONS: In patients with COVID-19, there was a higher proportion of women at high risk for preeclampsia at the first-trimester screening than in the general population, mainly because of maternal risk factors, rather than placental signs of a deficient trophoblastic invasion.

Implementation of routine first-trimester combined screening for preeclampsia based on the Gaussian algorithm: A clinical effectiveness study.

OBJECTIVE: To evaluate the clinical effectiveness of the routine first-trimester screening for preeclampsia (PE) after being implemented in six Catalan maternities. METHODS: Participants in the reference group were recruited prospectively between October 2015 and September 2017. Participants in the study group were recruited retrospectively between November 2018 and May 2019, after implementing the screening program. PE risk was assessed between 11 + 0 and 13 + 6 weeks of gestation using the Gaussian algorithm combining maternal characteristics, mean arterial blood pressure, uterine artery pulsatility index, and maternal serum pregnancy-associated plasma protein-A. Women with a risk ≥1/137 were prescribed daily salicylic acid (150 mg) until 36 weeks of gestation. RESULTS: Preterm PE occurred in 30 of 2641 participants (1.14%) in the reference group, as compared with 18 of 2848 participants (0.63%) in the study group (OR: 0.55; 95% CI, 0.31-0.99; P = 0.045). In the reference group, 37 participants (1.40%) were admitted to ICU, as compared with 23 participants (0.81%) in the study group (OR: 0.57; 95% CI, 0.34-0.96; P = 0.035). CONCLUSION: The routine first-trimester PE screening can be implemented in a public healthcare setting, leading to a significant reduction in the incidence of preterm PE and of maternal ICU admission.

Angiogenic factors for planning fetal surveillance in fetal growth restriction and small-for-gestational-age fetuses: A prospective observational study.

OBJECTIVE: The aim of this study was to assess the added value of the soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) ratio for adjusting the periodicity of ultrasound examinations in early-onset fetal growth restriction (FGR) and small for gestational age (SGA). DESIGN: A prospective, observational study. SETTING: Tertiary referral hospital. POPULATION: One hundred and thirty-four single pregnancies with ultrasonographic estimated fetal weight (EFW) below the 10th centile between 20+0 and 31+6  weeks of gestation with antegrade umbilical artery flow. METHODS: The time from Doppler and sFlt-1/PlGF assessment to delivery was recorded and classified into four ranges: <1, <2, <3 and <4 weeks. MAIN OUTCOME MEASURES: Sensitivity (Sn), specificity (Sp), positive predictive value (PPV) and negative predictive value (NPV) of sFlt-1/PlGF values to predict the time to delivery. RESULTS: In the SGA cohort, the NPV calculated for an sFlt-1/PlGF cut-off value of 38 was 100% for delivery before 3 weeks, and 98% for delivery before 4 weeks after diagnosis (95% CI 0.89-1.00). In the FGR cohort, the NPV calculated for an sFlt-1/PlGF cut-off value of 38 was 100% for delivery before 2 weeks after diagnosis (95% CI 0.92-1.00). By contrast, more than 50% of cases with an sFlt-1/PlGF value of >85 required an elective delivery before 1 week. CONCLUSIONS: sFlt-1/PlGF values in early-onset SGA and FGR are predictive of the time to delivery and could be used for planning fetal surveillance, by reducing the frequency of ultrasound in cases with sFlt-1/PlGF < 38 and by providing closer follow-up in cases with sFlt-1/PlGF >85. TWEETABLE ABSTRACT: sFlt-1/PlGF values in early-onset SGA/FGR could be used in addition to Doppler for planning fetal surveillance.

Diagnostic accuracy of the Gaussian first-trimester combined screening for pre-eclampsia to predict small-for-gestational-age neonates.

OBJECTIVE: Pre-eclampsia and delivery of small-for-gestational-age (SGA) neonates can be predicted from the first trimester. A Gaussian model for prediction of PE has recently been described, although its capacity to predict SGA is still unknown. METHODS: This was a secondary analysis of a prospective cohort study conducted at Vall d'Hebron University Hospital (Barcelona) in 2483 single pregnancies from October 2015 to September 2017. Mean arterial blood pressure and mean uterine artery pulsatility index were recorded at the first-trimester scan. Serum concentrations of placental growth factor and pregnancy-associated plasma protein-A were assessed between 8+0 and 13+6  weeks. The predictive capacities of early (<32 weeks) and preterm (<37 weeks) SGA were tested. RESULTS: For SGA without pre-eclampsia, detection rates of 25.0% (95% confidence interval [CI] 0-75.0) for early SGA and 14.3% (95% CI 3.6-28.6) for preterm SGA were achieved. For SGA with pre-eclampsia, the algorithm showed detection rates of 100.0% (95% CI 25.0-100.0) for early SGA and 56.3% (95% CI 31.3-81.3) for preterm SGA. CONCLUSION: This algorithm identifies 62.5% of early SGA and 27.3% of preterm SGA. Combined screening for predicting both pre-eclampsia and SGA by using the Gaussian algorithm is feasible and would simplify clinical practice.

Evaluating the Effect of Pravastatin in Early-Onset Fetal Growth Restriction: A Nonrandomized and Historically Controlled Pilot Study.

OBJECTIVE: This study aimed to analyze the effect of pravastatin on angiogenic factors, feto-maternal Doppler findings and pregnancy outcomes in women with early-onset fetal growth restriction (FGR) treated with pravastatin compared with nontreated controls. STUDY DESIGN: This was a pilot study conducted between March 2016 and September 2017. Women with single pregnancies and FGR diagnosed at ≤ 28 weeks of gestation were offered 40 mg of pravastatin daily. Doppler progression, soluble fms-like tyrosine kinase 1 (sFlt-1)/placental growth factor (PlGF) values, and pregnancy outcomes were assessed and compared with consecutive historical controls. Controls were matched to treated women for gestational age, maternal characteristics, maternal and obstetric history, Doppler severity classification, and angiogenic factors at diagnosis. The sFlt-1/PlGF was measured in maternal serum at two different times: before pravastatin was started (ratio M0) and during pravastatin treatment (ratio M1). Doppler severity was classified into four categories: normal, mild, moderate, and severe. RESULTS: A total of 38 women were enrolled in this study. No differences were observed in baseline characteristics between groups. However, when compared with the ratio M0, M1 was increased by a median (interquartile range) of 67.0 (-34.8 to 197.3) in the control group but decreased by a median (interquartile range) of -10.1 (-53.1 to -0.07) in the pravastatin treated group (p < 0.001). No significant differences were observed in Doppler progression throughout pregnancy. Median interval from diagnosis to delivery was extended by 16.5 days, the median newborn birthweight was increased from 1,040 to 1,300 g, and the number of women with preeclampsia decreased from 9 (47.4%) to 6 (31.6%) in treated women; however, these trends were not statistically significant. CONCLUSION: In women with early-onset FGR, treatment with pravastatin 40 mg daily was associated with significant improvement in the angiogenic profile. Additionally, median pregnancy duration and median birthweight increased and the incidence of PE was reduced in treated women. Nevertheless, since this pilot study was underpowered, none of these differences were statistically significant. KEY POINTS: · Pravastatin improves sFlt-1/PlGF in FGR.. · Pregnancy duration tended to be greater in treated women.. · Birthweight tended to be greater in treated women..

Soluble fms-like tyrosine kinase to placental growth factor ratio in different stages of early-onset fetal growth restriction and small for gestational age.

INTRODUCTION: Increased soluble fms-like tyrosine kinase to placental growth factor ratio (sFlt-1/PlGF) has been demonstrated in early-onset fetal growth restriction (FGR) and small for gestational age (SGA). sFlt-1/PlGF cut-offs have been described to assess preeclampsia severity; however, sFlt-1/PlGF values present in early-onset SGA and different FGR severity stages remain unknown. Hence, the objective of this study was to describe and compare the sFlt-1/PlGF values and pregnancy outcomes among early-onset SGA/FGR stages. MATERIAL AND METHODS: This is a prospective case-control study conducted at Vall d'Hebron University Hospital. Singleton pregnancies with estimated fetal weight <10th centile and a control group of uncomplicated pregnancies between 20+0 and 31+6  weeks of gestation were enrolled. Study women were classified at diagnosis into different stages, according to estimated fetal weight centile and Doppler ultrasound. sFlt-1/PlGF serum concentrations were measured at diagnosis and, together with pregnancy outcomes, were compared among FGR severity stages, SGA, and controls. Finally, correlations between sFlt-1/PlGF values and time to delivery, gestational age at delivery, days of neonatal admission, and birthweight z-scores were investigated. RESULTS: Among the 207 women enrolled, 32 (15.4%) had uncomplicated pregnancies, 49 (23.7%) pregnancies showed SGA, and 126 (60.9%) involved FGR (92 being stage I, 17 stage II, and 17 stage III). SGA and controls had similar median sFlt-1/PlGF values (25.7 vs 27.1, P > .05) and pregnancy outcomes. However, all FGR stages had significantly poorer outcomes and greater sFlt-1/PlGF values than those of SGA and controls. Furthermore, median values differed significantly among all FGR severity stages (9.76 for stage I; 284.3 for stage II, and 625.02 for stage III, P < .05) increasing with FGR severity as well as the frequency of adverse pregnancy outcomes. Additionally, a significant correlation was found between greater sFlt-1/PlGF ratio values and gestational age at delivery, time from diagnosis to delivery, birthweight z-scores, and time in neonatal intensive care unit (r = -.637, r = -.576, r = -.161, and r = .311, respectively). CONCLUSIONS: Values of sFlt-1/PlGF at diagnosis permit early-onset FGR/SGA severity classification with good correlation with Doppler ultrasound findings and the occurrence of adverse outcomes. Thus, sFlt-1/PlGF could aid in early-onset FGR/SGA severity classification and clinical management when Doppler assessment is not feasible.

Individual risk assessment for prenatal counseling in early-onset growth-restricted and small-for-gestational-age fetuses.

INTRODUCTION: Early-onset fetal growth restriction and small-for-gestational age of fetuses lead to an increased risk of adverse pregnancy outcomes. Doppler abnormalities can predict the occurrence of complications in the short term, but normal fetal Doppler values at the time of diagnosis do not exclude their occurrence in the long term. The objective of this study was to investigate the capacity of a predictive model to assess individual risks for prenatal counseling at the time of diagnosis. MATERIAL AND METHODS: This was a prospective observational study of singleton pregnancies with estimated fetal weight below the 10th centile between 20+0 and 31+6  weeks of gestational age. Placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) levels, estimated fetal weight centile, uterine artery pulsatility index, fetal Doppler and maternal risk factors for placental disease were assessed at the time of enrollment. The occurrence of adverse perinatal outcomes or the need for elective delivery at <30, <34 or <37 weeks was considered an adverse pregnancy outcomes. Univariable logistic regression analysis was used to examine the association between each predictive variable and the adverse outcomes. A multivariable logistic regression-based model was constructed with the combination of all variables. An additional model without sFlt-1/PlGF was also created. Both models, and the sFlt-1/PlGF alone, were used to develop the different formulas to assess individual risks. Receiver operating characteristic curves were constructed to assess and compare their performance of screening. RESULTS: Forty-nine small-for-gestational-age fetuses and 124 with fetal growth restriction were enrolled at a median gestational age of 23.6 weeks. Elective delivery was needed in 77 (44.5%) women at <37 weeks, 53 (30.6%) women at <34 weeks and 30 (17.3%) at <30 weeks. Adverse perinatal outcomes occurred in 81 (55.9%) pregnancies. When areas under the curve were compared among models, no statistically significant differences were observed between the model with sFlt-1/PlGF and sFlt-1/PlGF alone; however, the model without sFlt-1/PlGF yielded an overall poorer performance. CONCLUSIONS: Individual risk assessment can be made at the time of early-onset fetal growth restriction/small-for-gestational-age diagnosis, which permits accurate counseling of parents with an affected fetus. Two formulas could be used: one combining maternal characteristics and ultrasound findings and the other with a single sFlt-1/PlGF measurement.

Cut-off values for Gaussian first-trimester screening for early-onset preeclampsia with maternal history, biochemical markers and uterine artery Doppler.

INTRODUCTION: Several algorithms for first-trimester screening for preeclampsia are available; however, the Gaussian model algorithm is more likely to match the characteristics of different populations. It is recommended to validate a screening strategy before being implemented in clinical practice; unfortunately, the validation process might not be feasible in all settings. Thus, the aim of this study was to provide cut-off values for the Gaussian model for its use in clinical practice. MATERIAL AND METHODS: This prospective cohort study was conducted at Vall d'Hebron University Hospital (Barcelona) from October 2015 to September 2017. A total of 2641 women with singleton pregnancies were recruited. Recorded at the first-trimester scan were demographic characteristics, maternal obstetric history, maternal history, uterine artery Doppler and arterial blood pressure. Serum concentrations of pregnancy-associated plasma protein-A and placental growth factor were assessed from the first-trimester blood test. Detection rates and cut-off values for fixed 5%, 10 %, 15 %, 20 %, 25 % and 30 % false-positive rates were calculated for all combinations of markers. RESULTS: Ninety (3.41 %) of the 2641 women developed preeclampsia, which was early-onset in 11 (0.42 %). The cut-off values and their respective detection rates, for the screening of early-onset PE by all possible combinations of markers involved in this model, are provided. DISCUSSION: When external validation of first-trimester screening for preeclampsia before its clinical implementation is not feasible, the cut-off values from the Gaussian model algorithm provided in this study could be used and median values corrected prospectively if necessary.