Circulating angiogenic profiles and histo-morphological placental characteristics of uncomplicated post-date pregnancies

Introduction The objectives of this study were to describe the histo-morphology of post-date placentas in clinically uncomplicated pregnancies without adverse delivery outcomes and the association with maternal circulating pre-delivery Placental Growth Factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1), as well as the sFlt-1/PlGF ratio. Methods Post-date placentas (gestational week ≥40+2, n = 87) were macroscopically and histo-morphologically assessed according to the international, standardized Amsterdam Workshop Consensus Group criteria. Inter-rater agreement was evaluated by percentage of agreement. PlGF and sFlt-1 concentrations were available from maternal serum sampled close to delivery, and were compared by Mann-Whitney U test. Linear regression analyses were adjusted for predefined potential confounders. Results The majority of the post-date placentas showed morphological signs of delayed maturation. About half of the placentas showed increased syncytial knotting and fibrin. In placentas with increased presence of intervillous fibrin, median maternal PlGF level was significantly lower (p = 0.004), median sFlt-1 level higher and sFlt-1/PlGF ratio significantly higher (p = 0.002) compared to those with normal fibrin amounts. Increased placental syncytial knotting was associated with lower levels of PlGF, higher sFlt-1 and higher sFlt-1/PlGF ratio compared to those with normal knotting. Discussion Our standardized morphological study of post-date placentas in clinically healthy women with uncomplicated pregnancies and delivery outcomes revealed delayed maturation in the majority of placentas. Increased pre-delivery circulating anti-angiogenic profile was associated with increased intervillous fibrin and syncytial knotting. We propose that circulating maternal angiogenic biomarkers may be of future use in clinical post-date pregnancy assessment, as they reflect important aspects of placental health and function

The association between placenta-associated circulating biomarkers and composite adverse delivery outcome of a likely placental cause in healthy post-date pregnancies

Introduction Post-date pregnancies have an increased risk of adverse delivery outcome. Our aim was to explore the association between placenta-associated circulating biomarkers and composite adverse delivery outcome of a likely placental cause in clinically healthy post-date pregnancies. Material and methods Women with healthy singleton post-date pregnancies between 40+2 and 42+2 weeks of gestation were recruited to this prospective, observational study conducted at Oslo University Hospital, Norway (NCT03100084). Placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) were measured in the maternal serum samples closest to delivery. The composite adverse delivery outcome included fetal acidemia, low Apgar score (<4 at 1 min or <7 at 5 min), asphyxia, fetal death, assisted ventilation for more than 6 h, meconium aspiration, hypoxic–ischemic encephalopathy, therapeutic hypothermia, operative delivery due to fetal distress, or pathological placental histology findings. Two study-independent senior consultant obstetricians blinded to biomarker results concluded, based on clinical expert opinion, whether the adverse delivery outcomes were most likely associated with placental dysfunction (“likely placental cause”) or not. Means were compared using one-way analysis of variance and Bonferroni corrected pairwise comparisons between groups. Receiver operating characteristic (ROC) curves assessed the predictive ability of PlGF, sFlt-1/PlGF ratio, and PlGF <10th centile after adjustment for gestational age at blood sampling. Results Of 501 pregnancies reviewed for predefined adverse delivery outcomes and for a likely placental cause, 468 were healthy pregnancies and subsequently assigned to either the “uncomplicated” (no adverse outcome, n = 359), “intermediate” (non-placental cause/undetermined, n = 90), or “complicated” (likely placental cause, n = 19) group. There was a significant difference in mean PlGF and sFlt-1/PlGF ratio between the “complicated”, “intermediate”, and “uncomplicated” groups (108, 185, and 179 pg/mL, p = 0.001; and 48.3, 23.4, and 24.6, p = 0.002, respectively). There was a higher proportion of PlGF concentration <10th centile in the “complicated” group compared with the “intermediate” and “uncomplicated” groups (42.1% vs. 11.1% and 9.5%, p = 0.001). The largest area under the ROC curve for predicting “complicated” outcome was achieved by PlGF concentration and gestational age at blood sampling (0.76; 95% CI 0.65–0.86). Conclusions In clinically healthy post-date pregnancies, an antiangiogenic pre-delivery profile (lower PlGF level and higher sFlt-1/PlGF ratio) was associated with composite adverse delivery outcome of a likely placental cause

Predelivery placenta-associated biomarkers and computerized intrapartum fetal heart rate patterns

Background: Increasing syncytiotrophoblast stress in term and postdate placentas is reflected by increasing antiangiogenic dysregulation in the maternal circulation, with low “proangiogenic” placental growth factor concentrations and increased “antiangiogenic” soluble fms-like tyrosine kinase-1 concentrations. Imbalances in these placenta-associated proteins are associated with intrapartum fetal compromise and adverse pregnancy and delivery outcome. Cardiotocography is widely used to assess fetal well-being during labor, but it is insufficient on its own for predicting adverse neonatal outcome. Development of improved surveillance tools to detect intrapartum fetal stress are needed to prevent neonatal adverse outcome. Objective: This study aimed to assess whether predelivery circulating maternal angiogenic protein concentrations are associated with intrapartum computerized fetal heart rate patterns, as calculated by the Oxford System for computerized intrapartum monitoring (OxSys) 1.7 prototype. We hypothesized that in pregnancies with low “proangiogenic” placental growth factor levels, increased “antiangiogenic” soluble fms-like tyrosine kinase-1 levels, and increased soluble fms-like tyrosine kinase-1–placental growth factor ratio, the OxSys 1.7 prototype will generate more automated alerts, indicating fetal compromise. Our secondary objective was to investigate the relationship between maternal circulating placenta-associated biomarkers and rates of automated alerts in pregnancies with and without adverse neonatal outcome. Study Design: This was an observational prospective cohort study conducted at a single tertiary center from September 2016 to March 2020. Of 1107 singleton pregnancies (gestational week ≥37+0), 956 had available prelabor and predelivery placental growth factor and soluble fms-like tyrosine kinase-1 concentrations and intrapartum cardiotocography recordings. All neonatal and delivery outcomes were externally reviewed and categorized into 2 groups—the “complicated” group (n=32) and the “uncomplicated” group (n=924)—according to predefined adverse neonatal outcome. Eight different cardiotocography features were calculated by OxSys 1.7: baseline at start of cardiotocography, baseline at end of cardiotocography, short-term variation at start, short-term variation at end, nonreactive initial trace, and throughout the entire cardiotocography, maximum decelerative capacity, total number of prolonged decelerations, and OxSys 1.7 alert. OxSys 1.7 triggered an alert if the initial trace was nonreactive or if decelerative capacity and/or the number of prolonged decelerations exceeded a predefined threshold. Included women and attending clinicians were blinded to both biomarker and OxSys 1.7 results. Results: Mean maternal placental growth factor concentration was lower in the group with OxSys 1.7 alert compared with the group without the alert (151 vs 169 pg/mL; P=.04). There was a weak negative correlation between predelivery high soluble fms-like tyrosine kinase-1 and low short-term variation start (rs=−0.068; 95% confidence interval, −0.131 to −0.004; P=.036), predelivery high soluble fms-like tyrosine kinase-1 and low short-term variation end (rs=−0.068; 95% confidence interval, −0.131 to −0.005; P=.036), and high soluble fms-like tyrosine kinase-1–placental growth factor ratio and low short-term variation end (rs=−0.071; 95% confidence interval, −0.134 to −0.008; P=.027). The rate of decelerative capacity alerts increased more rapidly as placental growth factor decreased in the “complicated” compared with the “uncomplicated” group (0% to 17% vs 4% to 8%). Conclusion: More automated alerts indicative of fetal distress were generated by OxSys 1.7 in pregnancies with low maternal predelivery placental growth factor level, in line with likely increasing placental stress toward the end of the pregnancy. An antiangiogenic predelivery profile (lower placental growth factor) increased the rates of alerts more rapidly in pregnancies with adverse neonatal outcome compared with those without. We suggest that future studies developing and testing prediction tools for intrapartum fetal compromise include predelivery maternal placental growth factor measurements

Maternal placental growth factor and soluble fms-like tyrosine kinase-1 reference ranges in post-term pregnancies: A prospective observational study

Background Post-term pregnancies have increased risks for adverse fetal and maternal outcomes. Maternal concentrations of the placenta-associated proteins placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) have been identified as predictors for preeclampsia and fetal growth restriction, both syndromes of placental dysfunction. We have proposed that low maternal circulating PlGF and increased sFlt-1 are general markers for syncytiotrophoblast stress, which increases at and beyond term, even in apparently uncomplicated pregnancies. Our aim was to establish circulating PlGF, sFlt-1, and sFlt-1/PlGF reference ranges in healthy post-term pregnancies (gestational week ≥40+2), comparing with healthy term pregnancies and evaluating associations between time to delivery and biomarker percentiles. Methods Of 501 healthy, singleton post-term pregnancies prospectively recruited between September 2016 and December 2017 at our tertiary obstetric department, 426 with an uncomplicated delivery outcome contributed PlGF and sFlt-1 serum concentrations for reference range construction. A retrospective, cross-sectional, term group with an uncomplicated delivery outcome (n = 146) served as comparison. Differences in percentile values between groups and confidence intervals were calculated by quantile regression. Results In post-term pregnancies the 5th, 50th, and 95th percentiles for PlGF were: 70, 172, and 496 pg/mL; for sFlt-1: 2074, 4268, and 9141 pg/mL; and for sFlt-1/PlGF 5.3, 25.5, and 85.2. Quantile regression analyses comparing the post-term to the term group showed for PlGF a trend towards higher 10th through 30th percentiles, for sFlt-1 significantly higher 10th through 80th percentiles, and for sFlt-1/PlGF ratio significantly higher 30th percentile and significantly lower 95th percentile. PlGF below the 5th percentile and sFlt-1/PlGF ratio above the 95th percentile was associated with shorter time to delivery (p = 0.031 and p = 0.025, respectively). Conclusions Our findings support the concept of increasing syncytiotrophoblast stress post-term in clinically healthy pregnancies. Whether post-term dysregulated angiogenic markers reflect a biological placental clock merits further investigation