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.

Longitudinal change of sFlt-1/PlGF ratio in singleton pregnancy with early-onset fetal growth restriction.

OBJECTIVE: To describe the evolution of soluble fms-like tyrosine kinase-1 to placental growth factor (sFlt-1/PlGF) ratio in the last 5 weeks prior to delivery in singleton pregnancy complicated by early-onset fetal growth restriction (FGR), with or without pre-eclampsia (PE). METHODS: This was a prospective observational cohort study of early-onset FGR cases that underwent serial assessment of maternal serum sFlt-1/PlGF ratio from diagnosis to delivery. Measurements were made at weekly intervals and within the last 48 h before birth. Absolute values and percentage increase between time intervals were computed, and previously described cut-off values of 38 (suspicion of PE), 85 (aids diagnosis of PE) and 655 (high risk for imminent delivery) were used for analysis of the sFlt-1/PlGF ratio. We compared findings between cases with early-onset FGR only (n = 37) and those that additionally developed PE (n = 36). RESULTS: Overall perinatal survival was 63/73 (86.3%). A sFlt-1/PlGF ratio above 38 was observed 4 weeks before delivery in most FGR-only and FGR with PE cases (73% and 100%, respectively), but absolute values of sFlt-1/PlGF were significantly higher in FGR cases with PE. Extremely elevated values of the ratio (≥ 655) within the last 48 h before delivery were found in 65% of cases of FGR with PE, but in only 8% of isolated FGR cases (P < 0.001). CONCLUSION: Elevated sFlt-1/PlGF was observed in most early-onset FGR pregnancies from 4 weeks before delivery, and values were even higher if there was concurrent PE. However, serial measurements of the ratio were of limited value, being useful only to anticipate the need for imminent delivery in cases of FGR with PE when sFlt-1/PlGF values ≥ 655 were reached. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Screening for trisomies 21, 18 and 13 by cell-free DNA analysis of maternal blood at 10-11 weeks' gestation and the combined test at 11-13 weeks.

OBJECTIVE: To examine in a general population the performance of cell-free DNA (cfDNA) testing for trisomies 21, 18 and 13 at 10-11 weeks' gestation and compare it to that of the combined test at 11-13 weeks. METHODS: In 2905 singleton pregnancies, prospective screening for trisomies was performed by chromosome-selective sequencing of cfDNA in maternal blood at 10-11 weeks' gestation and by the combined test at 11-13 weeks' gestation. RESULTS: Median maternal age of the study population was 36.9 (range, 20.4-51.9) years. Results from cfDNA analysis were provided for 2851 (98.1%) cases and these were available within 14 days from sampling in 2848 (98.0%) cases. The trisomic status of the pregnancies was determined by prenatal or postnatal karyotyping or clinical examination of the neonates. Of the 2785 pregnancies with a cfDNA result and known trisomic status, cfDNA testing correctly identified all 32 cases with trisomy 21, nine of 10 with trisomy 18 and two of five with trisomy 13, with false-positive rates of 0.04%, 0.19% and 0.07%, respectively. In cases with discordant results between cfDNA testing and fetal karyotype, the median fetal fraction was lower than in those with concordant results (6% vs 11%). Using the combined test, the estimated risk for trisomy 21 was ≥ 1/100 in all trisomic cases and in 4.4% of the non-trisomic pregnancies. CONCLUSION: The performance of first-trimester cfDNA testing for trisomies 21 and 18 in the general population is similar to that in high-risk pregnancies. Most false-positive and false-negative results from cfDNA testing could be avoided if the a priori risk from the combined test is taken into account in the interpretation of individual risk.

Analysis of cell-free DNA in maternal blood in screening for fetal aneuploidies: updated meta-analysis.

OBJECTIVE: To review clinical validation or implementation studies of maternal blood cell-free (cf) DNA analysis and define the performance of screening for fetal trisomies 21, 18 and 13 and sex chromosome aneuploidies. METHODS: Searches of PubMed, EMBASE and The Cochrane Library were performed to identify all peer-reviewed articles on cfDNA testing in screening for aneuploidies between January 2011, when the first such study was published, and 4 January 2015. RESULTS: In total, 37 relevant studies were identified and these were used for the meta-analysis on the performance of cfDNA testing in screening for aneuploidies. These studies reported cfDNA results in relation to fetal karyotype from invasive testing or clinical outcome. Weighted pooled detection rates (DR) and false-positive rates (FPR) in singleton pregnancies were 99.2% (95% CI, 98.5-99.6%) and 0.09% (95% CI, 0.05-0.14%), respectively, for trisomy 21, 96.3% (95% CI, 94.3-97.9%) and 0.13% (95% CI, 0.07-0.20) for trisomy 18, 91.0% (95% CI, 85.0-95.6%) and 0.13% (95% CI, 0.05-0.26%) for trisomy 13, 90.3% (95% CI, 85.7-94.2%) and 0.23% (95% CI, 0.14-0.34%) for monosomy X and 93.0% (95% CI, 85.8-97.8%) and 0.14% (95% CI, 0.06-0.24%) for sex chromosome aneuploidies other than monosomy X. For twin pregnancies, the DR for trisomy 21 was 93.7% (95% CI, 83.6-99.2%) and the FPR was 0.23% (95% CI, 0.00-0.92%). CONCLUSION: Screening for trisomy 21 by analysis of cfDNA in maternal blood is superior to that of all other traditional methods of screening, with higher DR and lower FPR. The performance of screening for trisomies 18 and 13 and sex chromosome aneuploidies is considerably worse than that for trisomy 21.

Fetal fraction of cell-free DNA in maternal plasma in the prediction of spontaneous preterm delivery.

OBJECTIVES: To investigate whether, in pregnancies complicated by spontaneous preterm delivery, fetal fraction of cell-free DNA (cfDNA) in maternal plasma at 11-13 weeks' gestation is altered and if this measurement could be useful in the prediction of preterm delivery. METHODS: Fetal fraction of cfDNA was measured at 10 + 0 to 13 + 6 weeks' gestation in 3169 pregnancies, 3066 (96.7%) that delivered at ≥ 37 weeks and 103 (3.3%) with spontaneous delivery at < 37 weeks, including 21 that delivered at < 34 weeks and 82 that delivered at 34-37 weeks. The measured fetal fraction was converted to multiples of the median (MoM), corrected for maternal characteristics and gestational age, and the Mann-Whitney U-test was used to determine the significance of differences in the median values in the spontaneous preterm delivery groups from that in the term delivery group. RESULTS: In the spontaneous preterm delivery groups (< 34 weeks' gestation, 34-37 weeks, < 37 weeks), compared to the term delivery group, there was no significant difference in the median fetal fraction MoM (1.004, 0.922 and 0.946, respectively, vs 1.015). CONCLUSION: Measurement of fetal fraction in maternal plasma at 11-13 weeks' gestation is not predictive of spontaneous preterm delivery.

Analysis of cell-free DNA in maternal blood in screening for aneuploidies: meta-analysis.

OBJECTIVE: To review clinical validation or implementation studies of maternal blood cell-free (cf) DNA analysis in screening for aneuploidies and to explore the potential use of this method in clinical practice. METHODS: Searches of PubMed and MEDLINE were performed to identify all peer-reviewed articles on cfDNA testing in screening for aneuploidies between 2011, when the first such study was published, and 20 December 2013. RESULTS: Weighted pooled detection rates (DR) and false-positive rates (FPR) in singleton pregnancies were 99.0% (95% CI 98.2­99.6) and 0.08% (95% CI0.03­0.14), respectively, for trisomy 21; 96.8% (95% CI 94.5­98.4) and 0.15% (95% CI 0.08­0.25) for trisomy 18; 92.1% (95% CI 85.9­96.7) and 0.20% (95% CI 0.04­0.46) for trisomy 13; 88.6% (95% CI 83.0­93.1) and 0.12% (95% CI 0.05­0.24) for monosomy X, and 93.8% (95% CI 85.9­98.7) and 0.12% (95% CI 0.02­0.28) for sex chromosome aneuploidies other than monosomy X. For twin pregnancies, the DR was 94.4% (95% 74.2­99.0) and the FPR was 0% (95% CI 0.00­1.84) for trisomy 21. CONCLUSION: An analysis of cfDNA in maternal blood provides effective screening for trisomies.

Implementation of maternal blood cell-free DNA testing in early screening for aneuploidies.

OBJECTIVE: To explore the feasibility of routine maternal blood cell-free (cf) DNA testing in screening for trisomies 21, 18 and 13 at 10 weeks' gestation. METHOD: In this prospective study, women attending The Fetal Medicine Centre in London, UK, between October 2012 and April 2013, with singleton pregnancy and live fetus with CRL 32-45 mm, were screened for trisomies 21, 18 and 13 by cfDNA testing at 10 weeks and the combined test at 12 weeks. RESULTS: cfDNA testing was performed in 1005 singleton pregnancies with a median maternal age of 37 (range, 20-49) years. Risks for trisomies were provided for 957 (95.2%) cases and in 98.0% these were available within 14 days from sampling. In 48 (4.8%) cases no result was provided due to problems with delivery to the laboratory, low fetal fraction or assay failure. Repeat sampling was performed in 40 cases and a result obtained in 27 (67.5%) of these. In 11 cases the risk score for trisomy 21 and in five cases that for trisomy 18 was > 99%, in one the risk for trisomy 13 was 34% and in 968 the risk for each of the three trisomies was < 0.01%. The suspected trisomies were confirmed by karyotyping after chorionic villus sampling (CVS), except in one case of trisomy 18 in which the karyotype was normal. On the basis of the maternal age distribution of the study population, the expected and observed numbers for each of the three trisomies were similar. Both cfDNA and combined testing detected all trisomies, but the estimated false-positive rates (FPR) were 0.1% and 3.4%, respectively. CONCLUSION: Routine screening for trisomies 21, 18 and 13 by cfDNA testing at 10 weeks is feasible and has a lower FPR than does combined testing, but abnormal results require confirmation by CVS.

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.