Predicting Time to Delivery in Hypertensive Disorders: Assessing PlGF and sFlt-1 with the Novel Parameter 'Mtp-Multiples of a Normal Term Placenta'.

Background: Imbalanced angiogenesis is characteristic of normal placental maturation but it also signals placental dysfunction, underlying hypertensive disorders during pregnancy. This study aimed to investigate the relationship between angiogenic placental aging, measured by markers placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) using the new index "Multiples of a normal term placenta" (Mtp) and the duration of pregnancy. Methods: A retrospective observational study was conducted, including singleton pregnancies diagnosed or suspected of hypertensive disorders after the 20th gestational week. Mtp measures how far a single dosage of angiogenic marker deviates from the expected value in an uncomplicated full-term pregnancy (Mpt = sFlt-1/sFlt-1 reference value or PIGF/PIGF reference value). We considered the 90th, 95th, and 97.5th centiles for sFlt-1 and the 2.5th, 5th, and 10th centiles for PlGF as references. Results: The categories with longer time to delivery, regardless of gestational age, were: Mtp PlGF 10th c ≥ 2, ≥3 and Mtp sFlt-1 90th c ≤ 0.5 (median days of 9, 11, 15 days, respectively). These two categories Mtp sFlt-1 90th c ≥ 3 and Mtp sFlt-1 97.5th c ≥ 2 allow the identification of women at risk for imminent delivery within 1 day. Women who were deemed at low/medium risk based on the sFlt-1/PIGF ratio appeared to be at high risk when considering the individual values of sFlt-1 and/or PIGF. Conclusions: This new Mtp index for sFlt-1 and PlGF could be employed to assess the degree of placental aging in women with hypertensive disorders. It represents a valid tool for evaluating the risk of imminent birth, irrespective of gestational age, surpassing the current stratification based on the sFlt-1/PIGF ratio.

sFlt-1 Levels as a Predicting Tool in Placental Dysfunction Complications in Multiple Pregnancies.

BACKGROUND: several studies have demonstrated that angiogenic markers can improve the clinical management of hypertensive disorders (HDs) and fetal growth restriction (FGR) in singleton pregnancies, but few studies have evaluated the performance of these tests in multiple pregnancies. Our aim was to investigate the role of soluble fms-like tyrosine kinase 1 (sFlt-1) in predicting adverse obstetric outcomes in hospitalized multiple pregnancies with HD (preeclampsia/gestational hypertension/uncontrolled chronic hypertension) and/or FGR in one or more fetuses. METHODS: A retrospective analysis of multiple pregnancies with HD/FGR occurring after the 20th gestational week. Pregnant women were divided into two groups: women with high levels of sFlt-1 and those with low levels of sFlt-1. A value of sFlt-1 greater than or equal to 15,802 pg/mL was considered arbitrarily high, as it is equivalent to two times the 90th percentile expected in an uncomplicated full-term singleton pregnancy based on data from a prospective multicenter study (7901 pg/mL). RESULTS: The cohort included 39 multiple pregnancies. There were no cases of birth <34 weeks, HELLP syndrome, ICU admission, and urgent cesarean sections for HD/FGR complications reported among women with low levels of sFlt-1. CONCLUSIONS: A cut-off value of sFlt-1 ≥ 15,802 pg/mL could represent a valuable tool for predicting adverse obstetric outcomes in multiple pregnancies hospitalized for HD/FGR disorders, regardless of gestational age and chorionicity.

Imbalanced Angiogenesis in Pregnancies Complicated by SARS-CoV-2 Infection.

COVID-19 and preeclampsia (preE) share the ANG-II mediated endothelial dysfunction, resulting from a significant dysregulation of RAS and an imbalanced proportion of anti-angiogenic and pro-angiogenic soluble plasmatic factors. Of note, an increased incidence of preE has been reported among COVID-19-infected mothers compared to the general pregnant population. The two most promising angiogenic markers are the soluble fms-like tyrosine kinase receptor-1 (sFlt-1), the major antiangiogenic factor, and the placental growth factor (PlGF), a powerful angiogenic factor. Since these markers have proven useful in the prediction, diagnosis, and severity of preE, this study aimed to evaluate their maternal serum levels in pregnancies complicated by SARS-CoV-2 infection and to assess their potential use to guide the management of these women. A retrospective analysis of SARS-CoV-2-positive pregnant women was performed. The serum levels of sFlt-1 and PlGF were collected at the diagnosis of SARS-CoV-2 infection at the hospital, before the beginning of steroid/hydroxychloroquine and/or antithrombotic therapy. The sFlt-1/PlGF ratio was stratified using cut-off values clinically utilized in the diagnosis and prediction of preE (low < 38, intermediate 38−85/110* and high >85/110*, * if before or after the 34th week of gestation). A total of 57 women were included, of whom 20 (35%) had signs and symptoms of COVID-19 at hospital presentation and 37 (65%) were asymptomatic. None were vaccinated. The mean gestational age at diagnosis of SARS-CoV-2 infection was 32 weeks in symptomatic patients and 37 weeks and 5 days in asymptomatic ones (p = 0.089). sFlt-1 serum levels were higher in SARS-CoV-2 positive asymptomatic patients compared to women with COVID-19 related symptoms (4899 ± 4357 pg/mL vs. 3187 ± 2426 pg/mL, p = 0.005). sFlt-1/PlGF at admission was <38 in 18 of the 20 symptomatic women (90%) compared to 22 (59%) of the asymptomatic patients (p = 0.018). Of note, two of the three women admitted to the intensive care unit had a very low ratio (<2). In turn, rates of patients with sFlt-1/PlGF at admission > 85/110 were not significantly different between the two groups: 11% in asymptomatic patients (4/37) vs. none of the symptomatic patients (p = 0.286), and all of them presented a placental dysfunction, like preE (n = 1) and FGR (n = 3). Of note, there were no stillbirths or maternal or neonatal deaths among symptomatic patients; also, no cases of preE, FGR, or small for gestational age neonates were diagnosed. In conclusion, our data suggest that SARS-CoV-2 infection during pregnancy could influence the angiogenic balance. A significant pathological alteration of the sFlt-1/PlGF ratio cannot be identified during the symptomatic phase; however, if left untreated, SARS-CoV-2 infection could potentially trigger placental dysfunction.

Splenic artery aneurysm in obstetrical patients: A series of four cases with different clinical presentation and outcome.

OBJECTIVE: To describe four consecutive cases of splenic artery aneurysm (SAA) with different clinical patterns of presentation among obstetrical patients. METHODS: A series of four cases of SAA diagnosed in pregnant or postpartum women at our University center between January 1998 and December 2020. Clinical and radiologic data were retrospectively obtained by reviewing paper and electronic medical records after acquiring patient's consent. RESULTS: One case was completely asymptomatic and incidentally identified at the beginning of pregnancy, thus allowing for multidisciplinary treatment. The other three cases were unknown: two manifested with maternal collapse due to aneurysm rupture in the third trimester of gestation, whereas one presented with acute abdominal pain during the postpartum period and was successfully managed before rupture occurred. CONCLUSION: Although extremely rare, SAA rupture in obstetrical patients can be associated with dramatic consequences. Early suspicion and prompt intervention are essential to avoid fatal outcomes, so promotion of knowledge of all the potential clinical patterns of presentation of SAA rupture among obstetrical patients is mandatory.

sFlt-1/PlGF ratio in hypertensive disorders of pregnancy in patients affected by COVID-19.

OBJECTIVES: To analyze soluble Fms-like tyrosine Kinase 1 (sFlt-1) and Placental Growth Factor (PlGF) ratio concentrations in COVID-19 pregnant patients with and without Hypertensive Disorders of Pregnancy (HDP), compared with non COVID-19 pregnant patients with HDP and a control group. STUDY DESIGN: We recruited and obtained a complete follow-up of 19 COVID-19 pregnant patients with HDP and of 24 COVID-19 normotensive pregnant patients. Demographic, clinical and sFlt-1/PlGF ratio findings were compared with a group of 185 non COVID-19 pregnant patients with HDP and 41 non COVID normotensive patients. Findings were based on univariate analysis and on a multivariate adjusted model, and a case by case analysis of COVID-19 pregnant patients with an abnormal sFlt-1/PlGF ratio > 38 at recruitment. MAIN OUTCOME MEASURES: sFlt-1/PlGF ratio. RESULTS: We confirmed a significant higher prevalence of HDP in women affected by COVID-19 compared to control population. sFlt-1/PlGF ratio was found high in HDP patients, with and without of Sars-Cov2 infection. COVID-19 patients with worse evolution of the disease showed greater rates of obesity and other comorbidities. sFlt/PlGF ratio proved not to be helpful in the differential diagnosis of the severity of this infection. CONCLUSIONS: COVID-19 pregnant patients showed a higher prevalence of HDP compared to non COVID-19 controls, as well as higher comorbidity rates. In spite of the possible common endothelial target and damage, between Sars-Cov-2 infection and HDP, the sFlt1/PlGF ratio did not correlate with the severity of this syndrome.

Placental growth factor as a predictive marker of preeclampsia - PREBIO study - PREeclampsia BIOchemical study.

INTRODUCTION: To evaluate the clinical utility of placental growth factor (PlGF) for the prediction of preeclampsia (PE). MATERIALS AND METHODS: This prospective cohort study included women divided into three groups: (1) pregnancies without preconceptional risk of developing PE; (2) pregnancies with a preconceptional and/or current risk of developing PE; (3) PE-complicated pregnancies (control group). Blood samples were collected every 4-5 weeks or during hospitalization from early second trimester until delivery in the group 1 and 2, at the diagnosis of PE in the group 3. Plasma levels of PlGF were measured using The Triage PlGF test (Alere) and considered pathological under the 5th centile for gestational age. Sensitivity (Sn), specificity (Sp), positive and negative predictive value (PPV, NPV) were calculated. RESULTS: In group 1, 30% of women (3/10) had pathological test but none of them developed PE (Sp 70%, NPV 100%). In group 2 (n = 75), none of the patients with normal test developed PE (0/24), while 39% of women with PlGF < 5th centile (20/51) developed PE (Sn 100%, Sp 44%, PPV 39%, NPV 100%). In group 3 (n = 11) all women except one had a pathological PlGF test (Sn 90%, PPV 100%). CONCLUSIONS: Our data support recent studies which identify PlGF as a biochemical marker not only of PE, but also of placental dysfunction. In fact, it is useful for ruling out PE in women at risk because of the high Sn and high NPV: a normal PlGF is related with a positive pregnancy outcome. Therefore, the measurement of this biomarker would simplify PE clinical management and would reduce costs.

Letter to the Editor: SFlt-1 and PlGF Levels in Pregnancies Complicated by SARS-CoV-2 Infection.

We read with interest the work by Espino-y-Sosa and colleagues [...].

Management of pregnancy blood pressure increase in the emergency room: role of PlGF-based biochemical markers and relative economic impact.

INTRODUCTION: To evaluate the clinical and economic impact of healthcare management of pregnant women with blood pressure increase (BPI) accessing emergency room (ER) and the utility of the introduction of a PlGF-based test in clinical practice. MATERIALS AND METHODS: This retrospective cohort study included women with single pregnancies who performed at least 1 ER access for BPI after the 20th gestational week in 2016. BPI was subsequently classified as significant if associated with preeclampsia (PE) or Fetal Growth Restriction (FGR) and not significant otherwise. Two experts evaluated potential changes in patients' management with the introduction of a PlGF-based test. The direct healthcare cost was estimated. RESULTS: We enrolled 107 patients, of which 30% showed significant BPI (17 PE cases, 13 FGR, and 2 both pathologies). Anamnestic, clinical, and laboratory evaluations were not effective in differentiating between significant and not significant BPI (p-values: .8320, .2856, and .2297, respectively). The introduction of a PlGF-based test would have reduced overtreatment and undertreatment. The test would have avoided 18% of all hospitalizations, 35% of hospitalizations for BPI, 43% of outpatient referrals, and 13% of ER accesses. The number of avoidable accesses was higher in women with not significant BPI. Overall, the mean total cost (from first ER access until delivery) was €2634 per woman and €401 would have been avoidable. CONCLUSION: The clinical integration of PlGF-based tests is advantageous in diagnostic, prognostic and economic terms, as an objective marker of placental dysfunction.

PlGF in a clinical setting of pregnancies at risk of preeclampsia and/or intrauterine growth restriction.

Placental growth factor (PlGF) is an angiogenic molecule produced by the placenta and implicated in the pathogenesis of preeclampsia (PE) and intrauterine growth restriction (IUGR). We have evaluated utility and applicability of the PlGF test in a clinical setting of pregnancies at risk of PE or complicated by IUGR in order to assess its relationship with pregnancy outcomes. Seventy-three pregnancies were enrolled between 19 and 35 weeks: 57 pregnancies at risk of PE and 16 at diagnosis of IUGR. Maternal circulating PlGF levels were measured by the Triage PlGF test (Alere, San Diego, CA). Pregnancy outcomes were evaluated in relation to three categories of plasma PlGF levels: very low (<12 pg/ml), low (12-100 pg/ml) and normal (≥100 pg/ml). Uterine artery Doppler velocimetry (UADV) pulsatility index (PI) was measured in the same patients on the day of maternal sampling. Pregnancies at risk with very low plasma PlGF levels had significantly lower gestational age at delivery than patients with low or normal PlGF. The rate of emergency C-section was significantly higher in the group with PlGF <12 pg/ml. IUGR pregnancies with very low and low PlGF delivered earlier than patients with normal PlGF. All IUGR with very low and low PlGF had UADV PI > 95th percentile. Our data indicate that PlGF may provide useful information to identify fetuses requiring increased surveillance and possibly urgent delivery in pregnancies at risk of adverse outcomes. Furthermore, in IUGR, PlGF can predict adverse pregnancy outcomes that may be secondary to placental insufficiency.

Parental counseling in trisomy 18: Novel insights in prenatal features and postnatal survival.

Data on the outcome of trisomy T18 (T18) when diagnosed during pregnancy are lacking. We performed a retrospective study of pregnancies complicated by T18 diagnosed at our center and a literature search for publications on the topic, with pooled estimates of survival rates at different gestational and post-natal ages. In our series, all the 60 patients included in the analysis had prenatally detected ultrasound anomalies, which were evidenced in the first trimester or at the second trimester scan in 73% of cases. In the continued pregnancies, ultrasound findings did not correlate with prenatal or post-natal outcome. A meta-analysis of available literature and our data showed that 48% [37-60%] of fetuses were live born, and among these 39% [11-72%] survived beyond 48 hr and 11% [3-21%] beyond 1 month. Our results confirm that prenatal ultrasound has high sensitivity in detection of T18 but is not predictive of the outcome of the continued pregnancies. The data on survival support that T18, even when antenatally diagnosed, cannot be considered as a uniformly lethal syndrome.

Seasonal impact in the frequency of isolated spina bifida.

OBJECTIVES: To evaluate whether a relationship exists between season at conception and occurrence of isolated spina bifida (ISB). STUDY DESIGN: All fetuses with prenatal diagnosis of ISB were analyzed according to date of conception. We compared the seasonal rates of conception between ISB fetuses and a control group consisting of a cohort of fetuses delivered during the same period from 1992 to 2009. RESULTS: In the control group, conceptions were equally distributed among the four seasons. Chi-square analysis showed a significantly higher rate of ISB conceptions in the fall compared with the control group (16/36, 44% vs. 12467/50533, 25%, Odds Ratio (OR) 2.44, 95% confidence interval 1.21-4.92). Not a single woman with a fetus affected by ISB took preconceptional supplement of folic acid. CONCLUSIONS: Seasonality affects the frequency of ISB. We hypothesize that the seasonal differences may reflect dietary and climate changes with reduced intake of folic acid in the fall.

Influencing factors for late-onset preeclampsia.

OBJECTIVE: Different etiologies for early- (<34.0 weeks) and late (≥34.0 weeks)-onset preeclampsia (EO-LO PE) are reported. The aim of our study is to identify influencing factors for the LO form. METHODS: Retrospective study of 284 consecutive women diagnosed as preeclamptic at 22.4-41.5 weeks, from 3/2005 to 10/2011, evaluated in relation to EO versus LO PE. RESULTS: LO PE was identified in 151 cases. Gestational Diabetes Mellitus (11% versus 4%, p = 0.04), body mass index (BMI) ≥35 kg/m(2) (9% versus 2%, p = 0.03), pathological weight gain for BMI class (30% versus 13%, p = 0.001), ≥5 (58% versus 23%, p < 0.001) and ≥7 kg/m(2) BMI increase (19% versus 9%, p = 0.04) were more common in LO than in EO PE. At Estimation Regression analysis weighted for Gestational Age (GA) at delivery BMI ≥35 and ≥5 kg/m(2) BMI increase resulted related to LO PE (OR = 3.76, CI(95%) = 1.97-17.04; OR = 4.28, CI(95%) = 2.44-7.54). CONCLUSIONS: BMI ≥35 and ≥5 kg/m(2) increase appeared as influencing factors for LO PE, thus supporting the role of systemic inflammation in its pathogenesis.