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.

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.

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.

Next-Generation Sequencing Gene Panels and "Solo" Clinical Exome Sequencing Applied in Structurally Abnormal Fetuses.

OBJECTIVE: The aim of the study was to assess the diagnostic yield of 2 different next-generation sequencing (NGS) approaches: gene panel and "solo" clinical exome sequencing (solo-CES), in fetuses with structural anomalies and normal chromosomal microarray analysis (CMA), in the absence of a known familial mutation. METHODOLOGY: Gene panels encompassing from 2 to 140 genes, were applied mainly in persistent nuchal fold/fetal hydrops and in large hyperechogenic kidneys. Solo-CES, which entails sequencing the fetus alone and only interpreting the Online Mendelian Inheritance in Man genes, was performed in multisystem or recurrent structural anomalies. RESULTS: During the study period (2015-2020), 153 NGS studies were performed in 148 structurally abnormal fetuses with a normal CMA. The overall diagnostic yield accounted for 35% (53/153) of samples and 36% (53/148) of the fetuses. Diagnostic yield with the gene panels was 31% (15/49), similar to 37% (38/104) in solo-CES. CONCLUSIONS: A monogenic disease was established as the underlying cause in 35% of selected fetal structural anomalies by gene panels and solo-CES.

Polymorphisms of genes involved in homocysteine metabolism in preeclampsia and in uncomplicated pregnancies.

OBJECTIVE: To evaluate the possible relationship between preeclampsia and polymorphisms in the main genes involved in folate-homocysteine metabolism. STUDY DESIGN: Case-control study: 43 patients with preeclampsia and 122 controls without pregnancy complications. Laboratory studies: tHcy and other amino acids, folate and vitamin B(12) and polymorphisms: 677C > T and 1298A > C (MTHFR); 699C > T, 844ins68 and 1080C > T (CBS); 2756A > G (MTR); and 66G > A, IVS1+766G > A and IVS1+754A > C (MTRR). RESULTS: Plasma tHcy and folate values were significantly higher (P = 0.004 and P = 0.019), while Met/tHcy ratios were lower (P < 0.001) in the patients compared with controls. No association was observed between polymorphisms tested and preeclampsia. In the control group, four such associations were found: the 1298A > C polymorphism (MTHFR) with the ratio Met/tHcy (P = 0.014); the 699C > T polymorphism (CBS) with the ratio tHcy/SigmaAA (P = 0.013); the 2756A > G polymorphism (MTR) with tHcy (P = 0.034); and the IVS1+766G > A polymorphism (MTRR) with hyperhomocysteinemia (P = 0.012). CONCLUSION: An association between the polymorphisms analysed and preeclampsia could not be demonstrated.

Are plasma total homocysteine and other amino acids associated with glucose intolerance in uncomplicated pregnancies and preeclampsia?

OBJECTIVE: To evaluate the possible association between plasma total homocysteine or other amino acid concentrations and gestational diabetes or glucose intolerance (GI), in normotensive and preeclamptic pregnant women. STUDY DESIGN: Prospective study including 243 pregnant women without previous risk factors. O'Sullivan test (plus oral glucose tolerance test when necessary) was performed, and homocysteine, B vitamins and plasma amino acids (AA) were measured at 24-25 weeks. Homocysteine and other amino acids were also measured in the third trimester. RESULTS: Significant differences were observed in the incidence of preeclampsia in relation to abnormal glucose tolerance (P < 0.012). In normotensive patients, the glucose intolerance group showed significantly lower tHcy (P = 0.021) and increased plasma alanine concentrations in comparison with controls (P = 0.046), although no correlation was observed between both amino acid concentrations. CONCLUSIONS: (a) A higher incidence of preeclampsia was observed in abnormal glucose tolerance patients, (b) total homocysteine and alanine were the only individual amino acids whose plasma concentrations varied according to the glucose tolerance classes, and (c) an association between hyperhomocysteinemia and glucose intolerance in our preeclamptic patients could not be demonstrated.

Perinatal outcome prediction by maternal homocysteine and uterine artery Doppler velocimetry.

OBJECTIVES: (a) To evaluate the predictive value of uterine Doppler velocimetry for pregnancy complications, (b) to study the relationship between abnormal uterine Doppler velocimetry and plasma homocysteine, and (c) to determine whether homocysteine measurement improves the predictive value of uterine Doppler screening. STUDY DESIGN: Prospective study including 94 pregnant women without previous risk factors. Total homocysteine, folate and Vitamin B(12) were analysed. Uterine Doppler velocimetry at weeks 24-25 was performed. RESULTS: The presence of any uterine Doppler alteration had a sensitivity of 66.7%, and a specificity of 81.2%, in predicting obstetric complications. The likelihood ratio was 3.6. The positive and negative predictive values were 27.3 and 95.8%, respectively. The global efficiency was 83.0%. The addition of hyperhomocysteinemia to Doppler alterations increased the sensitivity from 66.7 to 77.8%. CONCLUSIONS: The addition of homocysteine determination to uterine Doppler evaluation in the second trimester does not usefully improve its predictive value.

[Hyperhomocysteinemia during pregnancy as a risk factor of preeclampsia]. / Hiperhomocisteinemia durante el embarazo como factor de riesgo de preeclampsia.

A revision about the role of hyperhomocysteinemia in the development of preeclampsia is presented, which summarises our experience in different biochemical and genetic points in relation to this possible association. Plasma total homocysteine concentrations (tHcy) during pregnancy were significantly lower than those of non-pregnant women: 2nd trimester (median, 5.3 micromol/l; range, 3.1-10.0 micromol/l); 3rd trimester (median, 6.3 micromol/l; range, 3.2-13.0 micromol/l). Hyperhomocysteinemia (tHcy>P95) was established as values higher than 7.7 micromol/l in the 2nd trimester, and as values higher than 10.5 micromol/l in the 3rd trimester of pregnancy. We found an association between hyperhomocysteinemia and preeclampsia: tHcy values were significantly higher in the preeclamptic group than in uncomplicated pregnancies; the OR for preeclampsia in hyperhomocysteinemic patients was 7.7 (CI 95%, 1.7-34.8). The other amino acid concentrations were also higher in preeclamptic women. The negative correlation observed between homocysteine and folate in the control group, was not present in preeclamptic women. An association between homocysteine concentrations in preeclampsia and glucose intolerance was not observed. The Doppler study of uterine artery flow velocity waveforms seems to be a good screening method to identify pregnancies at high risk of preeclampsia. The addition of homocysteine determination did not usefully improve its predictive value. The polymorphisms in the main genes involved in folate-homocysteine metabolism studied could not be considered as the determinants of the hyperhomocysteinemia observed in preeclamptic pregnants.

Hiperhomocisteinemia durante el embarazo como factor de riesgo de preeclampsia / Hyperhomocysteinemia during pregnancy as a risk factor of preeclampsia

Se presenta una revisión sobre el papel que la hiperhomocisteinemia tiene en el desarrollo de preeclampsia, aportando nuestra experiencia en diferentes aspectos bioquímicos y genéticos relacionados con el tema. Las concentraciones de homocisteína plasmática total (Hct) observadas en gestantes son inferiores a las de mujeres fértiles no gestantes: 2.o trimestre (mediana, 5,3 µmol/l; rango, 3,1-10 µmol/l); 3.er trimestre (mediana, 6,3 µmol/l; rango, 3,2-13,0 µmol/l). Definimos hiperhomocisteinemia (Hct > P95) durante el embarazo toda concentración > 7,7 µmol/l (2.o trimestre) y >10,5 µmol/l (3.er trimestre).Encontramos asociación entre hiperhomocisteinemia y preeclampsia: la Hct es significativamente superior en el grupo de preeclampsias que en los controles; odds ratio (OR) para preeclampsia en hiperhomocisteinémicas = 7,7 (intervalo de confianza [IC] 95 por ciento, 1,7-34,8). Las preeclampsias muestran también un aumento generalizado del resto de los aminoácidos. La correlación negativa observada en gestantes controles entre homocisteína y folato no se observa en las preeclámpticas. No hemos encontrado asociación entre las concentraciones de homocisteína en las preeclámpticas y la intolerancia a la glucosa. La velocimetría Doppler de arterias uterinas en el 2.o trimestre es un método que puede ser útil para identificar a gestantes con riesgo de preeclampsia. La adición de la determinación de Hct no mejora significativamente su predictibilidad. Los polimorfismos en los genes implicados en el metabolismo de la homocisteína estudiados no pueden ser considerados como determinantes de la hiperhomocisteinemia observada en las gestantes con preeclampsia (AU)

Homocysteine and other plasma amino acids in preeclampsia and in pregnancies without complications.

OBJECTIVES: To evaluate a). the plasma amino acid changes observed in pregnant women (n = 124) and b). the homocysteine and other amino acid changes in preeclampsic patients (n = 18), and to determine c) whether these changes were also evident in nonpregnant women with a prior history of preeclampsia (n = 18). DESIGN AND METHODS: Case-control study. Plasma total homocysteine (tHcy): HPLC with fluorescence detection, and amino acids (AA): ion exchange chromatography. RESULTS: a). Significantly lower absolute AA values were observed in the pregnant controls for homocysteine, total, essential, and nonessential AA compared with nonpregnant controls. b. In preeclampsia, significantly higher absolute values of tHcy, total, essential and nonessential AA were observed, but relative values referred to total AA were not different. These changes corrected after delivery. CONCLUSIONS: Hyperhomocysteinemia and an increase in most AA levels were observed in preeclampsia. Relative AA values suggested that these changes might be explained by fluctuations in plasma volume. Abnormal AA levels corrected after delivery.

Plasma total homocysteine in uncomplicated pregnancy and in preeclampsia.

OBJECTIVES: (a) To establish the reference values for plasma total homocysteine in our pregnant population. (b) To determine the possible association between hyperhomocysteinemia and preeclampsia in our geographical area. STUDY DESIGN: Control-case study with 32 preeclamptic patients and 64 controls without pregnancy complications. Plasma total homocysteine, determined by HPLC (fluorescence detection), was correlated with serum folate and Vitamin B(12) (analyzed by competitive protein binding chemiluminescent assay). STATISTICAL ANALYSES: Mann-Whitney, Wilcoxon and Spearman test (SPSS, 10.0). RESULTS: Homocysteine concentrations in the controls were significantly higher while folate was significantly lower in the third trimester of pregnancy when compared with the second (P<0.0001). Homocysteine and folate values were significantly higher in patients compared with controls in the third trimester (P=0.005 and 0.005, respectively). The OR for preeclampsia in hyperhomocysteinemia was 7.7 (95% CI: 1.7-34.8). CONCLUSION: Pregnant women with hyperhomocysteinemia have a 7.7-fold risk for preeclampsia (CI 95%: 1.7-34.8) compared with normal controls.

Homocisteína y gestación / Homocysteine and pregnancy

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