Prediction of perinatal survival in early-onset fetal growth restriction: role of placental growth factor.

OBJECTIVE: To analyze the ability to predict perinatal survival and severe neonatal morbidity of cases with early-onset fetal growth restriction (eoFGR) using maternal variables, ultrasound parameters and angiogenic markers at the time of diagnosis. METHODS: This was a prospective observational study in a cohort of singleton pregnancies with a diagnosis of eoFGR (< 32 weeks of gestation). At diagnosis of eoFGR, complete assessment was performed, including ultrasound examination (anatomy, biometry and Doppler assessment) and maternal serum measurement of the angiogenic biomarkers, soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF). Logistic regression models for the prediction of perinatal survival (in cases diagnosed at < 28 weeks) and severe neonatal morbidity (in all liveborn cases) were calculated. RESULTS: In total, 210 eoFGR cases were included, of which 185 (88.1%) survived perinatally. The median gestational age at diagnosis was 27 + 0 weeks. All cases diagnosed at ≥ 28 weeks survived. In cases diagnosed < 28 weeks, survivors (vs non-survivors) had a higher gestational age (26.1 vs 24.4 weeks), estimated fetal weight (EFW; 626 vs 384 g), cerebroplacental ratio (1.1 vs 0.9), PlGF (41 vs 18 pg/mL) and PlGF multiples of the median (MoM; 0.10 vs 0.06) and lower sFlt-1/PlGF ratio (129 vs 479) at the time of diagnosis (all P < 0.001). The best combination of two variables for predicting perinatal survival was provided by EFW and PlGF MoM (area under the receiver-operating-characteristics curve (AUC), 0.84 (95% CI, 0.75-0.92)). These were also the best variables for predicting severe neonatal morbidity (AUC, 0.73 (95% CI, 0.66-0.80)). CONCLUSIONS: A model combining EFW and maternal serum PlGF predicts accurately perinatal survival in eoFGR cases diagnosed before 28 weeks of gestation. Prenatal prediction of severe neonatal morbidity in eoFGR cases is modest regardless of the model used. © 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

sFlt-1/PlGF ratio and timing of delivery in early-onset fetal growth restriction with antegrade umbilical artery flow.

OBJECTIVE: To analyze the value of the soluble fms-like tyrosine kinase-1/placental growth factor (sFlt-1/PlGF) ratio in predicting the time to delivery in early-onset fetal growth restriction (FGR) with preserved antegrade umbilical artery (UA) flow at diagnosis. METHODS: This was a prospective observational single-center cohort study of pregnancies with early-onset (< 32 + 0 weeks) FGR and antegrade UA flow, in which maternal serum sFlt-1/PlGF ratio was determined at diagnosis. FGR was defined as estimated fetal weight < 3rd centile or < 10th centile with UA pulsatility index > 95th centile, fetal middle cerebral artery pulsatility index < 5th centile or cerebroplacental ratio < 5th centile. The previously described sFlt-1/PlGF ratio cut-off value of 85 for facilitating the diagnosis of pre-eclampsia was assessed in the prediction of the need to deliver in < 1 week and ≥ 4 weeks. RESULTS: In total, 120 cases were included. There were 116 (96.7%) liveborn neonates and 108 (90.0%) perinatal survivors. Median (interquartile range (IQR)) gestational age at diagnosis of early-onset FGR was 27.1 (25.7-29.4) weeks. Median (IQR) sFlt-1/PlGF ratio at diagnosis was 196 (84-474). Ninety (75.0%) cases had a sFlt-1/PlGF ratio ≥ 85. Among pregnancies with a liveborn neonate, median (IQR) interval to delivery in the groups with sFlt-1/PlGF ratio < 85 and ≥ 85 was 41 (22-54) days and 11 (4-20) days, respectively (P < 0.01). The probability of having to deliver within 1 week after diagnosis was 0% and 35.6% in those with sFlt-1/PlGF ratio < 85 and ≥ 85, respectively (P = 0.03), and the probability of delaying delivery for ≥ 4 weeks was 72.4% and 19.5%, respectively (P < 0.01). CONCLUSION: sFlt-1/PlGF ratio < 85 at diagnosis of early-onset FGR with antegrade UA flow identifies a group of pregnancies in which the need to deliver within 1 week is very low and the interval to delivery is expected to be prolonged for ≥ 4 weeks in > 70% of cases. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Uterine artery Doppler and sFlt-1/PlGF ratio: prognostic value in early-onset pre-eclampsia.

OBJECTIVE: To evaluate the performance of the mean uterine artery pulsatility index (UtA-PI) and the automated measurement of the soluble fms-like tyrosine kinase-1 (sFlt-1)/placental growth factor (PlGF) ratio for the prognostic assessment of both maternal and perinatal outcomes, and the time-to-delivery interval in early-onset (≤ 34 + 0 weeks) pre-eclampsia (PE) cases with attempted expectant management. METHODS: Fifty-one singleton pregnancies with early-onset PE were enrolled in the study. Mean UtA-PI and sFlt/PlGF ratio were measured at diagnosis. The association of each marker and their combinations with adverse maternal and perinatal outcomes was assessed by univariable comparisons and multivariable logistic regression analysis and time-to-delivery interval by survival analysis. RESULTS: Twenty-six (51%) had adverse maternal outcome and 14 (27%) had adverse perinatal outcome. At the time of onset of PE, only gestational age was significantly related to maternal complications. Gestational age at onset, mean UtA-PI and sFlt-1/PlGF ratio were significantly associated with perinatal complications, their combination reaching a sensitivity of 64% with 95% specificity, and an area under the receiver-operating characteristics curve of 0.89 (95% CI, 0.79-0.99). Regarding the time until delivery, 92% (12/13) of cases with sFlt-1/PlGF ratio > 655 and 39% (15/38) of cases with a ratio ≤ 655 delivered within the first 48 h, 8% (1/13) and 19% (7/38), respectively, delivered between 48 h and 7 days and 0% (0/13) and 42% (16/38), respectively, delivered after 7 days. CONCLUSION: Mean UtA-PI and sFlt-1/PlGF ratio in combination with gestational age are useful for the prognostic assessment of perinatal complications at the time of diagnosis of early-onset PE, but this combination has limited value for the prediction of maternal complications. Moreover, sFlt-1/PlGF ratio > 655 is closely related to the need to deliver within 48 h. [[ArtCopyrightmsg]].

Uterine artery Doppler and sFlt-1/PlGF ratio: usefulness in diagnosis of pre-eclampsia.

OBJECTIVE: To evaluate the usefulness of the mean pulsatility index of the uterine arteries (mPI-UtA) and automated measurement of the soluble fms-like tyrosine kinase 1 (sFlt-1)/placental growth factor (PlGF) ratio on suspicion or at diagnosis of pre-eclampsia (PE). METHODS: Patients with singleton pregnancies with PE (n = 60) diagnosed according to current recommendations, or with suspected PE (n = 32) defined by (1) blood pressure (BP) ≥ 160/100 mmHg, (2) BP ≥ 140/90 mmHg or proteinuria, together with suggestive clinical symptoms or (3) intrauterine growth restriction (IUGR) at < 34 + 0 weeks, were enrolled and mPI-UtA and the sFlt-1/PlGF ratio were measured. Values > 95(th) centile were considered abnormal. All cases were classified according to occurrence of PE and/or IUGR and subclassified, depending on gestational age at delivery, as early (< 34 + 0 weeks) or late (≥ 34 + 0 weeks). RESULTS: PE was confirmed in 72 cases, in which 32 early deliveries occurred. Isolated IUGR was diagnosed in nine early cases and one late case, while the remaining 10 cases were late deliveries without PE or IUGR. In pregnancies in which PE and IUGR were excluded, mPI-UtA was abnormal in 40% but the sFlt-1/PlGF ratio was normal in 100%. In early PE, mPI-UtA at diagnosis was abnormal in 100% of cases with IUGR and in 91% without IUGR, while sFlt-1/PlGF was abnormal in 100% and 96%, respectively. In late PE, mPI-UtA was abnormal in 50% and 37% of cases with and without IUGR while the sFlt-1/PlGF ratio was abnormal in 50% and 26%, respectively. CONCLUSION: Abnormal mPI-UtA and sFlt-1/PlGF ratio are common in early PE. In late PE, mPI-UtA is normal in most cases and thus not diagnostically useful. The sFlt-1/PlGF ratio shows high specificity but low sensitivity to confirm PE when suspected.

Predictive value of sequential models of uterine artery Doppler in pregnancies at high risk for pre-eclampsia.

OBJECTIVE: To evaluate the performance of models described previously for the prediction of pre-eclampsia (PE), based on the sequential evaluation of uterine artery resistance at 11-13 weeks and 19-22 weeks, in a high-risk population. METHODS: This was a prospective study in 135 women with singleton pregnancies and at least one of the following high-risk conditions: PE and/or intrauterine growth restriction in a previous pregnancy, chronic hypertension, pregestational diabetes, renal disease, body mass index > 30 kg/m(2) , autoimmune disease (systemic lupus erythematosus, antiphospholipid syndrome or rheumatoid arthritis) and thrombophilia. Mean uterine artery pulsatility index (mUtA-PI) at 11-13 and at 19-22 weeks' gestation was measured and analyzed according to quantitative and semi-quantitative models, to predict late PE (resulting in delivery ≥ 34 weeks) and early PE (delivery < 34 weeks). RESULTS: Late PE developed in 21 (15.6%) pregnancies and early PE in six (4.4%). Using mUtA-PI, the detection rates of late and early PE for a false-positive rate of 10% were 14.3% and 33.3%, respectively, at 11-13 weeks, and 19.0% and 66.7%, respectively, at 19-22 weeks. Using a semi-quantitative approach, the group of pregnant women with mUtA-PI ≥ 90(th) percentile at both 11-13 and 19-22 weeks had a greater risk for early PE (odds ratio, 21.4 (95% CI, 2.5-184.7)) compared with the group with mUtA-PI < 90(th) percentile at both periods. Using a quantitative approach, there was relative worsening in the mUtA-PI (multiples of the median) from the first to the second trimester in all cases of early PE. CONCLUSION: The application of semi-quantitative and especially quantitative models to evaluate sequential changes in uterine artery Doppler findings between the first and second trimesters could be of additional value in assessing high-risk women regarding their true risk of developing early PE.

Clinical implementation of the sFlt-1/PlGF ratio to identify preeclampsia and fetal growth restriction: A prospective cohort study.

OBJECTIVE: To analyze the usefulness of a clinical protocol for early detection of preeclampsia and/or fetal growth restriction (PE/FGR) using, in previously selected pregnancies, the measurement of the sFlt-1/PlGF ratio at 24-28 weeks of gestation. STUDY DESIGN: Prospective observational cohort study carried out in a single tertiary hospital in Spain. 5601 consecutive singleton pregnancies with complete follow-up were included. High-risk women for PE/FGR were selected by combining data from maternal history and second trimester uterine artery Doppler. Subsequently these patients underwent intensive monitoring, including the measurement of the sFlt-1/PlGF ratio at 24-28 weeks to predict PE/FGR. MAIN OUTCOME MEASURES: Early, intermediate and late PE/FGR (delivery <32 + 0, 32 + 0 - <36 + 0 and ≥36 + 0 weeks, respectively). RESULTS: Overall incidence of early, intermediate and late PE/FGR was 0.3%, 0.7% and 3.2%, respectively, being higher in the 4.3% of women selected for intensive monitoring: 5.8%, 8.7% and 15.4%, respectively (all p < 0.001). The area under the curve (AUC) with 95%CI of the sFlt-1/PlGF ratio for detecting early PE/FGR was 0.98 (0.97-1.00), and the sFlt-1/PlGF ratio >95th centile showed a sensitivity (%) of 100 (95%CI, 78.5-100) and specificity (%) of 80.6 (95%CI, 75.0-85.2). The AUC of the sFlt-1/PlGF ratio for detecting intermediate and late PE/FGR was of 0.87 (95%CI, 0.77-0.97) and 0.68 (95%CI, 0.58-0.79), respectively. CONCLUSION: A contingent strategy of measuring the sFlt-1/PlGF ratio at 24-28 weeks in women previously selected by clinical factors and uterine artery Doppler enables an accurate prediction of PE/FGR. This performance is optimal to predict PE/FGR requiring delivery before 32 weeks.

The role of angiogenic biomarkers and uterine artery Doppler in pregnant women with systemic lupus erythematosus or antiphospholipid syndrome.

OBJECTIVE: To evaluate the usefulness of the uterine artery mean pulsatility index (mPI-UtA) and the sFlt-1/PlGF ratio in women with systemic lupus erythematosus (SLE) or antiphospholipid syndrome (APS) for the prediction of placental dysfunction-related adverse outcomes (AO), namely pre-eclampsia (PE) and intrauterine growth restriction (IUGR), and for differential diagnosis between PE and SLE flares. STUDY DESIGN: Observational prospective cohort study of 57 pregnant women with SLE or APS. MAIN OUTCOME MEASURES: mPI-UtA and sFlt-1/PlGF ratio in maternal serum were obtained at four gestational age periods (11-14, 19-22, 24-29 and 32-34 weeks). Comparisons among pregnancies with normal outcome, SLE flare and AO were performed. RESULTS: Overall, we had 44 ongoing pregnancies (36 with SLE and 8 with APS) of which most (n = 35, 80%) were uncomplicated. The overall rate of AO was 9% (n = 4), that was diagnosed at a mean (SD) gestational age of 34.1 (7.5) weeks. Five SLE patients (14%) suffered a SLE flare. No differences for these markers were found between normal pregnancies and those affected by SLE flare. mUtA-PI values were significantly higher in the AO group when compared with normal and SLE flare groups, at 19-22 weeks (1.52, 0.95 and 0.76) and 32-34 weeks (1.13, 0.68 and 0.65), respectively. The sFlt-1/PlGF ratio was significantly higher in the AO group at 24-29 weeks (191.1, 3.1 and 9.2), respectively. CONCLUSION: Our preliminary results indicate that mPI-UtA and sFlt1/PlGF ratio may be useful to predict AO in women with SLE, and to make the differential diagnosis with a lupus flare.