Placental Growth Factor Testing Research Articles

Association of Low Levels of Placental Growth Factor and Fetal Growth Restriction in a Setting With a High Prevalence of Diabetes [ID 2683431

INTRODUCTION: Placental growth factor (PlGF) is a glycosylated protein from the vascular endothelial growth factor (VEGF) family that is involved in placental angiogenesis. In cases of placental dysfunction, decreased maternal serum PlGF levels predict the development of pregnancy complications such as preeclampsia, fetal growth restriction (FGR), and stillbirth. METHODS: Datasets from 114 high-risk patients who had clinical indication for PlGF testing from 2021 to 2023 were collected retrospectively. The anonymized dataset comprises PlGF test results categorized by gestational age-specific ranges and FGR categorized by percentile. Chi-squared analysis of 114 patients was used to assess the association between PlGF levels and FGR (less than 10th percentile). This study was approved by REb-USask #Bio3702. RESULTS: Of the 114 patients, 21 (18.4%) with low/very low PlGF and 8 (7.1%) with borderline/normal PlGF had fetuses with FGR less than 10th percentile. There was a significant difference between groups with a low/very low PlGF and normal PlGF levels (P<.001). The negative predictive value (NPV) for development of FGR less than 10% was 97.54%. CONCLUSION: Data collection is ongoing; however, in our patient population with a high prevalence of diabetes, preliminary data from 114 patients suggest that gestational age-stratified maternal serum PlGF levels have high NPV value for development of FGR less than 10th percentile. The implementation of this simple laboratory test in rural and remote communities would allow for earlier identification of pregnancies that require more intensive surveillance at a high-risk center of care.

Association of Low Levels of Placental Growth Factor With Abnormal Fetal Doppler Assessment [ID 2683423

INTRODUCTION: Placental growth factor (PlGF) is involved in placental angiogenesis and maturation. Low maternal serum PlGF levels predict placental dysfunction and associated conditions, such as preeclampsia, and fetal growth restriction. These pregnancy complications can lead to abnormal fetal Doppler assessment, indicating progressive fetal deterioration prompting preterm delivery. METHODS: We collected retrospective data from laboratory results of PlGF levels and fetal Dopplers (umbilical artery [UA], middle cerebral artery [MCA], and ductus venosus [DV]) from patients who had clinical indication for PlGF testing. Over 100 patients were identified to have results of all assessments between 2021 and 2023. Levels of PlGF were stratified in five categories according to gestational age and compared with normal and abnormal doppler results. For comparisons, the values were aggregated in normal and low PlGF. RESULTS: There were statistically significant associations between PlGF levels and Dopplers. Patients with low PlGF (less than 5th percentile for gestational age) were more likely to have abnormal dopplers than patients with normal PlGF (UA, P<.001; MCA, P<.001; DV, P<.001). A normal PlGF had a high negative predictive value (NPV) for normal dopplers (UA, 88%; MCA, 94.3%; DV, 98.6%). CONCLUSION: The results show that normal PlGF is highly associated with normal Dopplers. Additional data will be required to account for confounding factors; however, our preliminary data suggest that PlGF could be a useful tool for patients in rural and remote locations, as normal PlGF has a statistically and clinically significant negative predictive value for normal Doppler assessment.

Trends in antenatal corticosteroid administration: did our timing improve?

We aimed to analyze trends in the rate of effective antenatal corticosteroid prophylaxis (ACS) administrations across a spectrum of typical diagnoses associated with preterm birth. In this retrospective study we utilized delivery data after ACS from 2014 to 2020 at Charité Berlin, Germany. We evaluated the rate of effective ACS administrations defined as≤10days between last dose of ACS and delivery as well as the rate of post-ACS births on/after 37+0weeks. We explored conditions associated with high rates of ineffective ACS administrations (>10days before delivery). We analyzed the trend of ACS-effectiveness during the study period in the overall cohort and in placental dysfunction and cervical insufficiency diagnoses. The overall rate of effective ACS administrations was 42 % (709/1,672). The overall percentage of deliveries after/at 37+0weeks following ACS administration was 19 % (343). Placenta previa, twin pregnancy and isthmocervical insufficiency were associated with ineffective ACS (19-34 % effective i.e.≤10days before delivery). The overall ratio of effective ACS applications rose over time (p=0.002). Over the course of this study ACS effectiveness increased in placental dysfunction and isthmocervical insufficiency diagnoses (p=0.028; p=0.001). Compared to a previous publication we founda decrease of post-ACS deliveries after/at 37+0weeks (19 vs. 27 %). Ineffective ACS administrations are still frequent in patients with placenta previa, twin pregnancy and isthmocervical insufficiency. It remains to be investigated in future trials if the introduction of new diagnostic tools such as soluble Fms-like tyrosinkinase-1/placental growth factor (sFlt-1/PlGF) testing and placental alpha-microglobulin-1 (PAMG-1) testing directly led to an increased ACS effectiveness.

Perspectives on the Use of Placental Growth Factor (PlGF) in the Prediction and Diagnosis of Pre-Eclampsia: Recent Insights and Future Steps.

Pre-eclampsia (PE) is a complex multisystem disease of pregnancy that is becoming increasingly recognized as a state of angiogenic imbalance characterized by low concentrations of placental growth factor (PlGF) and elevated soluble fms-like tyrosine kinase (sFlt-1). PlGF is a protein highly expressed by the placenta with vasculogenic and angiogenic properties, which has a central role in spiral artery remodeling and the development of a low-resistance placental capillary network. PlGF concentrations are significantly lower in women with preterm PE, and these reduced levels have been shown to precede the clinical onset of disease. Subsequently, the clinical utility of maternal serum PlGF has been extensively studied in singleton gestations from as early as 11 to 13 weeks' gestation, utilizing a validated multimarker prediction model, which performs superiorly to the National Institute for Health and Care Excellence (NICE) and American College of Obstetricians and Gynecologists (ACOG) guidelines in the detection of preterm PE. There is extensive research highlighting the role of PlGF-based testing utilizing commercially available assays in accelerating the diagnosis of PE in symptomatic women over 20 weeks' gestation and predicting time-to-delivery, allowing individualized risk stratification and appropriate antenatal surveillance to be determined. "Real-world" data has shown that interpretation of PlGF-based test results can aid clinicians in improving maternal outcomes and a growing body of evidence has implied a role for sFlt-1/PlGF in the prognostication of adverse pregnancy and perinatal events. Subsequently, PlGF-based testing is increasingly being implemented into obstetric practice and is advocated by NICE. This literature review aims to provide healthcare professionals with an understanding of the role of angiogenic biomarkers in PE and discuss the evidence for PlGF-based screening and triage. Prospective studies are warranted to explore if its implementation significantly improves perinatal outcomes, explore the value of repeat PlGF testing, and its use in multiple pregnancies.

PlGF (Placental Growth Factor) testing in clinical practice – identifying the optimal threshold

Accurate diagnosis of preterm preeclampsia (PE) may improve the management of affected pregnancies. Previous studies have demonstrated that reduced levels of Placental growth factor (PlGF) levels (< 100 pg/mL) provide superior diagnostic performance to evaluate pregnant individuals with suspected hypertension. A single cut-off may not provide optimal test interpretation, since PlGF levels vary considerably across gestational age (GA) range. Our group recently generated centile curves for PlGF levels by combining data from Toronto and Cambridge, UK. We compared the diagnostic accuracy of GA-specific percentile values of PlGF, vs. a single cutoff of 100 pg/mL, in the setting of diagnostic testing for suspected preeclampsia in a single high-risk pregnancy center. Secondary analysis of published data in 979 high-risk pregnant women with singleton pregnancies evaluated between 2017-2019 at Mount Sinai Hospital, Toronto, Canada. PlGF testing was performed between 20+0 and 35+6 weeks of gestation. We compared the diagnostic accuracy of PlGF< 100 pg\mL vs. PlGF< 2.5% for GA. Primary outcomes were prediction of early-onset PE and preterm birth (PTB)< 32 weeks’ gestation. Overall, 374 (38.2%) had a normotensive pregnancy, 244 (24.9%) developed gestational hypertension19.3%, 189 () developed late-onset PE, and 172 (17.6%) developed early-onset PE. PlGF< 2.5% for GA provided better sensitivity with comparable specificity for diagnosis of early-onset PE and PTB< 32 weeks, when compared to a single threshold of 100 pg\mL, thereby improving the area under the ROC curve (Figure 1). Table 1 compares adjusted odds ratios (aOR) for maternal and fetal outcomes, between PlGF interpretation methods. Compared to PlGF< 100 pg\mL., PlGF < 2.5% for GA increased aOR for early-onset PE and PTB< 32 weeks (58.2 vs to 95.1 and 15.7 vs. 20.6 respectively). Low PlGF levels in high-risk pregnant women are strongly associated with adverse pregnancy outcomes. Adopting a PlGF < 2.5% for GA interpretation approach provides better diagnostic accuracy for the diagnosis of early-onset PE and PTB< 32 weeks.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Combination of PLGF and PAPPA as a biochemical markers to the first trimester maternal screening

Screening of fetal chromosomal abnormalities is an essential part of antenatal care. Effective first trimester screening involves PAPP-A (pregnancy associated plasma protein A) and free HCG (human chorionic gonadotropin) levels in the maternal serum along with ultrasound examination. The objective of this study is to investigate whether the measurement of PLGF (Placental Growth Factor) can improve the performance of first trimester combined screening for Trisomy 21, 18 and 13. A total of 350 samples were collected from pregnant women during the first trimester between 10 to 14 weeks of gestation. The ultrasound (US) data were collected from all cases which include US gestational age, NT value, CRL, and fetus number, if any. Blood samples were collected and tested for PAPP-A and free HCG tests. The combined risk of trisomy 21, 18 and 13 were calculated using PRISCA software. The screen positive cases (more than a defined cutoff rate) were stored at -20oC for PLGF testing. A total of 97 cases, including low and high risk patients were analyzed for PLGF. A significant reduction was observed among the risk group p ≤ 0.005 when compared to the negative control group. A positive correlation between PLGF and PAPPA was identified (r=0.69) p ≤0.001. In conclusion the study provide data indicating that inclusion of serum PLGF improve the performance of first trimester combined test for screening of Trisomy 21, 18 and 13 risk

Diagnostic utility of serial circulating placental growth factor levels and uterine artery Doppler waveforms in diagnosing underlying placental diseases in pregnancies at high risk of placental dysfunction

Placental pathology assessment following delivery in pregnancies complicated by preeclampsia, fetal growth restriction, abruption, and stillbirth reveals a range of underlying diseases. The most common pathology is maternal vascular malperfusion, characterized by high-resistance uterine artery Doppler waveforms and abnormal expression of circulating maternal angiogenic growth factors. Rare placental diseases (massive perivillous fibrinoid deposition and chronic histiocytic intervillositis) are reported to have high recurrence risks, but their associations with uterine artery Doppler waveforms and angiogenic growth factors are presently ill-defined. To characterize the patterns of serial placental growth factor measurements and uterine artery Doppler waveform assessments in pregnancies that develop specific types of placental pathology to gain insight into their relationships with the timing of disease onset and pregnancy outcomes. A retrospective cohort study conducted between January 2017 and November 2021 included all singleton pregnancies with at least 1 measurement of maternal circulating placental growth factor between 16 and 36 weeks' gestation, delivery at our institution, and placental pathology analysis demonstrating diagnostic features of maternal vascular malperfusion, fetal vascular malperfusion, villitis of unknown etiology, chronic histiocytic intervillositis, or massive perivillous fibrinoid deposition. Profiles of circulating placental growth factor as gestational age advanced were compared between these placental pathologies. Maternal and perinatal outcomes were recorded. A total of 337 pregnancies from 329 individuals met our inclusion criteria. These comprised placental pathology diagnoses of maternal vascular malperfusion (n=109), fetal vascular malperfusion (n=87), villitis of unknown etiology (n=96), chronic histiocytic intervillositis (n=16), and massive perivillous fibrinoid deposition (n=29). Among patients who developed maternal vascular malperfusion, placental growth factor levels gradually declined as pregnancy progressed (placental growth factor <10th percentile at 16-20 weeks' gestation in 42.9%; 20-24 weeks in 61.9%; 24-28 weeks in 77%; and 28-32 weeks in 81.4%) accompanied by mean uterine artery Doppler pulsatility index >95th percentile in 71.6% cases. Patients who developed either fetal vascular malperfusion or villitis of unknown etiology mostly exhibited normal circulating placental growth factor values in association with normal uterine artery Doppler waveforms (mean [standard deviation] pulsatility index values: fetal vascular malperfusion, 1.14 [0.49]; villitis of unknown etiology, 1.13 [0.45]). Patients who developed either chronic histiocytic intervillositis or massive perivillous fibrinoid deposition exhibited persistently low placental growth factor levels from the early second trimester (placental growth factor <10th centile at 16-20 weeks' gestation in 80% and 77.8%, respectively; 20-24 weeks in 88.9% and 63.6%; 24-28 weeks in 85.7% and 75%), all in combination with normal uterine artery Doppler waveforms (mean pulsatility index >95th centile: chronic histiocytic intervillositis, 25%; massive perivillous fibrinoid deposition, 37.9%). Preeclampsia developed in 83 of 337 (24.6%) patients and was most common in those developing maternal vascular malperfusion (54/109, 49.5%) followed by chronic histiocytic intervillositis (7/16, 43.8%). There were 29 stillbirths in the cohort (maternal vascular malperfusion, n=10 [9.2%]; fetal vascular malperfusion, n=5 [5.7%]; villitis of unknown etiology, n=1 [1.0%]; chronic histiocytic intervillositis, n=7 [43.8%]; massive perivillous fibrinoid deposition, n=6 [20.7%]). Most patients experiencing stillbirth exhibited normal uterine artery Doppler waveforms (21/29, 72.4%) and had nonmaternal vascular malperfusion pathologies (19/29, 65.5%). By contrast, 28 of 29 (96.5%) patients experiencing stillbirth had ≥1 low placental growth factor values before fetal death. Serial circulating maternal placental growth factor tests, in combination with uterine artery Doppler waveform assessments in the second trimester, may indicate the likely underlying type of placental pathology mediating severe adverse perinatal events. This approach has the potential to test disease-specific therapeutic strategies to improve clinical outcomes. Serial placental growth factor testing, compared with uterine artery Doppler studies, identifies a greater proportion of patients destined to have a poor perinatal outcome because diseases other than maternal vascular malperfusion are characterized by normal uteroplacental circulation.

Value of soluble fms-like tyrosine kinase-1/placental growth factor test in third trimester of pregnancy for predicting preeclampsia in asymptomatic women.

To estimate the value of screening maternal serum soluble fms-like tyrosine kinase/placental growth factor (sFlt-1/PlGF) ratio in asymptomatic women during 3rd trimester to predict preeclampsia (PE) development. The investigated group comprised of 178 pregnant women. During this gestation, 24 cases had developed PE and 12 isolated gestational hypertension (GH); whereas 142 remained normotensive. Blood samples were collected between 180 and 259 gestational days (g.d.) when the participants were asymptomatic. Serums were analyzed using the BRAHMS sFlt-1 Kryptor/BRAHMS PlGF plus Kryptor PE ratio test (Thermo Fisher Scientific, Henningdorf, Germany). High-risk pregnancies for the PE development were defined as sFlt-1/PlGF>38. The detection rate (DR) for manifestation of PE≤30days after sampling was 83.3% and overall DR during pregnancy 58.3%. Ten of 15 women having false positive prediction of PE suffered from GH, preterm birth and/or delivery of a small-for-gestational-age-newborn. False positive rate was significantly higher at 239-253 g.d. compared to sampling at 210-224 g.d. and 225-238 g.d. (21.9% vs. 7.8% and 5.3%; p < 0.05). The sFlt-1/PlGF test during 180-259 g.d. detected approximately half of subsequent PE cases. An optimal time to use the test for screening purposes was estimated 225-238 g.d. (DR 66.7%). False positive test results were more common to cases with other adverse pregnancy outcomes and samples drawn at higher gestational age.

Phenotype-Directed Management of Hypertension in Pregnancy.

Hypertensive disorders of pregnancy are among the most serious conditions that pregnancy care providers face; however, little attention has been paid to the concept of tailoring clinical care to reduce associated adverse maternal and perinatal outcomes based on the underlying disease pathogenesis. This narrative review discusses the integration of phenotype‐based clinical strategies in the management of high‐risk pregnant patients that are currently not common clinical practice: real‐time placental growth factor testing at Mount Sinai Hospital, Toronto and noninvasive hemodynamic monitoring to guide antihypertensive therapy at the University of Washington Medical Center, Seattle. Future work should focus on promoting more widespread integration of these novel strategies into obstetric care to improve outcomes of pregnancies at high risk of adverse maternal‐fetal outcomes from these complications of pregnancy.

Enhancing the value of the sFlt-1/PlGF ratio for the prediction of preeclampsia: Cost analysis from the Belgian healthcare payers' perspective.

To evaluate the economic impact of introducing the soluble fms-like tyrosine kinase (sFlt-1) to placental growth factor (PlGF) ratio test into clinical practice in Belgium for the prediction of preeclampsia (PE). We developed a one-year time-horizon decision tree model to evaluate the short-term costs associated with the introduction of the sFlt-1/PlGF test for guiding the management of women with suspected PE from the Belgian public healthcare payers' perspective. The model estimated the costs associated with the diagnosis and management of PE in pregnant women managed in either a test scenario, in which the sFlt-1/PlGF test is used in addition to current clinical practice, or a no test scenario, in which clinical decisions are based on current practice alone. Test characteristics were derived from PROGNOSIS, a non-interventional study in women presenting with clinical suspicion of PE. Unit costs were obtained from Belgian-specific sources. The main model outcome was the total cost per patient. Introduction of the sFlt-1/PlGF ratio test is expected to result in a cost saving of €712 per patient compared with the no test scenario. These savings are generated mainly due to a reduction in unnecessary hospitalizations. The sFlt-1/PlGF test is projected to result in substantial cost savings for the Belgian public healthcare payers through reduction of unnecessary hospitalization of women with clinical suspicion of PE that ultimately do not develop the condition. The test also has the potential to ensure that women at high risk of developing PE are identified and appropriately managed.

P-011. sFLT-1, PLGF e sFLT-1/PLGF levels in preeclampsia: correlation with mediated maternal results

To evaluate the economic impact of introducing the soluble fms-like tyrosine kinase (sFlt-1) to placental growth factor (PlGF) ratio test into clinical practice in Belgium for the prediction of preeclampsia (PE).Study design: We developed a one-year time-horizon decision tree model to evaluate the short-term costs associated with the introduction of the sFlt-1/PlGF test for guiding the management of women with suspected PE from the Belgian public healthcare payers’ perspective. The model estimated the costs associated with the diagnosis and management of PE in pregnant women managed in either a test scenario, in which the sFlt-1/PlGF test is used in addition to current clinical practice, or a no test scenario, in which clinical decisions are based on current practice alone. Test characteristics were derived from PROGNOSIS, a non-interventional study in women presenting with clinical suspicion of PE. Unit costs were obtained from Belgian-specific sources. The main model outcome was the total cost per patient.Introduction of the sFlt-1/PlGF ratio test is expected to result in a cost saving of €712 per patient compared with the no test scenario. These savings are generated mainly due to a reduction in unnecessary hospitalizations.The sFlt-1/PlGF test is projected to result in substantial cost savings for the Belgian public healthcare payers through reduction of unnecessary hospitalization of women with clinical suspicion of PE that ultimately do not develop the condition. The test also has the potential to ensure that women at high risk of developing PE are identified and appropriately managed.

Placental growth factor in assessment of women with suspected pre-eclampsia to reduce maternal morbidity: a stepped wedge cluster randomised control trial (PARROT Ireland)

ObjectiveTo determine whether the addition of placental growth factor (PlGF) measurement to current clinical assessment of women with suspected pre-eclampsia before 37 weeks' gestation would reduce maternal morbidity without increasing...

Placental growth factor as a diagnostic tool for placental mediated fetal growth restriction.

Placental growth factor (PlGF) has shown promise in identification of placental fetal growth restriction (FGR). We aimed to investigate the association between PlGF and sonographic markers of placental dysfunction and assess its ability to diagnose FGR secondary to maternal vascular malperfusion (MVM). A retrospective study of singleton pregnancies with small for gestational age (SGA) fetuses, who had PlGF testing at 16-36weeks. Fetuses with major chromosomal and/or structural anomalies and pregnancies with missing outcomes were excluded. Sonographic characteristics, perinatal outcomes and placental histopathology were compared between pregnancies with normal and low PlGF (<10th percentile for gestational age). The diagnostic accuracy of PlGF for prediction of MVM was calculated. 130 fetuses met inclusion criteria. Compared to normal PlGF (n=65), pregnancies with low PlGF (n=65) were associated with an estimated fetal weight<5th centile (73.8% (48) vs 53% (35), respectively, p=0.01), abnormal uterine, umbilical and MCA Dopplers (p=0.001 for all), fetal demise (18.8% (12) vs 0% respectively, p=0.01) and preterm delivery (100% (65) vs 39% (59), respectively, p<0.001) . Low PlGF had a 70.1% (58.6-80.0) sensitivity and a 79.6% (64.7-90.2) specificity for identifying MVM, with an AUC of 0.73 (0.63-0.84). Positive and negative predictive values were 85.7% (76.8-91.2) and 60.3% (51.2-68.9), respectively. PlGF outperformed other parameters of placental FGR (uterine, umbilical artery, middle cerebral artery and abdominal circumference<5th centile), in isolation and when combined. PlGF is a useful tool to aid in the diagnosis of placental FGR secondary to MVM.

A literature review and best practice advice for second and third trimester risk stratification, monitoring, and management of pre‐eclampsia

A literature review and best practice advice for second and third trimester risk stratification, monitoring, and management of pre‐eclampsia

A prognostic model to guide decision-making on timing of delivery in late preterm pre-eclampsia: the PEACOCK prospective cohort study.

Pre-eclampsia affects around 2-3% of all pregnancies, and is associated with potential serious complications for the woman and the baby. Once diagnosed, progression of the syndrome can be unpredictable, and decisions around timing of delivery need to take into account evolving maternal complications and perinatal morbidity. Novel prognostic models and blood biomarkers for determination of need for delivery in pregnancies with pre-eclampsia are now emerging. The objective of the study was to establish a prognostic model to inform optimal timing of delivery in women with late preterm pre-eclampsia (34+ 0 to 36+ 6 weeks' gestation), comparing novel candidate biomarkers (e.g. placental growth factor) with clinical and routinely collected blood/urinary parameters [incorporated into the PREP-S (Prediction models for Risk of Early-onset Pre-eclampsia - Survival) model] to determine clinically indicated need for delivery for pre-eclampsia (or related complications) within 7 days of assessment. Prospective recruitment of women in whom blood samples for placental growth factor and soluble fms-like tyrosine kinase-1 testing was obtained, alongside clinical data, for use within the PREP-S model. Candidate variables were compared using standard methods (sensitivity, specificity, receiver operator curve areas). Estimated probability of early delivery from PREP-S was compared with actual event rates by calibration. The PEACOCK (Prognostic indicators of severe disEAse in women with late preterm pre-eClampsia tO guide deCision maKing on timing of delivery) study was a prospective cohort study, nested within the PHOENIX (Pre-eclampsia in HOspital: Early iNductIon or eXpectant management) trial. Women between 34+ 0 and 36+ 6 weeks' gestation, with a diagnosis of pre-eclampsia, in whom a plasma (ethylenediaminetetraacetic acid) blood sample for placental growth factor testing was obtained, alongside clinical data for the assessment of variables in a prognostic model. Clinically indicated need for delivery for pre-eclampsia within 7 days of assessment. Statistical analysis: both PREP-S and placental growth factor were assessed and compared using standard methods (sensitivity and specificity for placental growth factor thresholds of 100 pg/ml and < 12 pg/ml, and receiver operating characteristic areas for continuous measurements). The estimated probability of early delivery from PREP-S was compared with actual event rates for women with similar probabilities by calibration. Calibration using logistic regression was also used. Between 27 April 2016 and 24 December 2018, 501 women were recruited to the study. Although placental growth factor testing had high sensitivity (97.9%) for delivery within 7 days, the negative predictive value was only 71.4% and the specificity was low (8.4%). The area under the curve for the clinical prediction model (PREP-S) and placental growth factor in this cohort in determining need for delivery within 7 days was 0.64 (standard error 0.03) and 0.60 (standard error 0.03), respectively, and 0.65 (standard error 0.03) in combination. A high proportion of women in this cohort already had low placental growth factor concentrations at the time of confirmed diagnosis, which reduced the ability of the biomarker to further predict adverse outcomes. In this group of women with late preterm pre-eclampsia, placental growth factor measurement is not likely to add to the current clinical assessment to help plan care for late preterm pre-eclampsia regarding timing of delivery. Existing models developed in women with early-onset pre-eclampsia to predict complications cannot be used to predict clinically indicated need for delivery in women with late preterm pre-eclampsia. Further statistical modelling and subgroup analysis is being considered to assess if improved model performance in the whole cohort or a subgroup can be achieved. Addition of other biomarkers to the model may also be of use and will be explored. Current Controlled Trials ISRCTN01879376. This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 30. See the NIHR Journals Library website for further project information.

PlGF (Placental Growth Factor) Testing in Clinical Practice: Evidence From a Canadian Tertiary Maternity Referral Center.

[Figure: see text].

A comparative study of two immunoassays of maternal placental growth factor

Circulating maternal levels of placental growth factor correlates well with placental function and numerous studies advocate its role to help rule-out preterm pre-eclampsia. A number of automated immunoassay platforms to quantify placental growth factors are currently available. The aim of this study was to highlight the importance of developing and validating appropriate reference ranges and clinical cut-offs for immunoassays, by comparing the results obtained from two different immunoassays of placental growth factor; the Quantikine® ELISA and the automated Triage® test. This was a secondary subgroup analysis of samples collected as part of a prospective cross-sectional study of placental growth factors in twin pregnancy. Consenting pregnant women with a twin pregnancy, across a variety of gestations, had a single blood sample taken at a one-time point only during their pregnancy. The plasma was initially biobanked and then later analysed in batches using both immunoassays. Although the placental growth factor values of the two immunoassays correlated well (r = 0.88, n = 178, p < .001), the actual results obtained were significantly different (mean difference 238.1 pg/ml). Poor concordance between the two immunoassays was also present, with the Triage® test recording 36 cases as <100 pg/ml whereas the Quantikine® ELISA identified only 4 as <100 pg/ml. Biomarker levels may vary significantly between different immunoassay platforms, highlighting the importance of developing validated clinical cut-offs for any automated immunoassay before its clinical application. These differences need to be understood to facilitate clinical utility given that placental growth factor testing is likely to be introduced into widespread clinical practice.

Placental growth factor testing in the management of late preterm preeclampsia without severe features: a multicenter, randomized, controlled trial

In women with late preterm preeclampsia, the optimal time for delivery remains a controversial topic, because of the fine balance between the maternal benefits from early delivery and the risks for prematurity. It remains challenging to define prognostic markers to identify women at highest risk for complications, in which case a selective, planned delivery may reduce the adverse maternal and perinatal outcomes. This trial aimed to determine whether using an algorithm based on the maternal levels of placental growth factor in women with late preterm preeclampsia to evaluate the best time for delivery reduced the progression to preeclampsia with severe features without increasing the adverse perinatal outcomes. This parallel-group, open-label, multicenter, randomized controlled trial was conducted at 7 maternity units across Spain. We compared selective planned deliveries based on maternal levels of placental growth factor at admission (revealed group) and expectant management under usual care (concealed group) with individual randomization in singleton pregnancies with late preterm preeclampsia from 34 to 36+6 weeks' gestation. The coprimary maternal outcome was the progression to preeclampsia with severe features. The coprimary neonatal outcome was morbidity at infant hospital discharge with a noninferiority hypothesis (noninferiority margin of 10% difference in incidence). Analyses were conducted according to intention-to-treat. Between January 1, 2016, and December 31, 2019, 178 women were recruited. Of those women, 88 were assigned to the revealed group and 90 were assigned to the concealed group. The data analysis was performed before the completion of the required sample size. The proportion of women with progression to preeclampsia with severe features was significantly lower in the revealed group than in the concealed group (adjusted relative risk, 0.5; 95% confidence interval, 0.33-0.76; P=.001). The proportion of infants with neonatal morbidity was not significantly different between groups (adjusted relative risk, 0.77; 95% confidence interval, 0.39-1.53; P=.45). There is evidence to suggest that the use of an algorithm based on placental growth factor levels in women with late preterm preeclampsia leads to a lower rate of progression to preeclampsia with severe features and reduces maternal complications without worsening the neonatal outcomes. This trade-off should be discussed with women with late preterm preeclampsia to allow shared decision making about the timing of delivery.

Prognostic indicators of severe disease in late preterm pre-eclampsia to guide decision making on timing of delivery: The PEACOCK study.

To assess the diagnostic performance of angiogenic biomarkers in determining need for delivery in seven days in women with late preterm preeclampsia. In a prospective observational cohort study in 36 maternity units across England and Wales, we studied the diagnostic accuracy of placental growth factor (PlGF) and sFlt-1 in determining the risk of complications requiring delivery in late preterm (34+0 to 36+6 weeks' gestation) preeclampsia. Angiogenic biomarkers were measured using the Quidel (PlGF) and Roche (sFlt-1:PlGF ratio) assays. Additional clinical data was obtained for use within the established 'Prediction of complications in early-onset pre-eclampsia' (PREP)-S prognostic model. Biomarkers were assessed using standard methods (sensitivity, specificity, Receiver Operator Curve areas). Estimated probability of early delivery from PREP-S was compared to actual event rates. Clinically indicated need for delivery for pre-eclampsia within seven days. PlGF (Quidel) testing had high sensitivity (97.9%) for delivery within seven days, but negative predictive value was only 71.4%, with low specificity (8.4%), with similar results from sFlt-1/PlGF assay. The area under the curve for PlGF was 0.60 (SE 0.03), and 0.65 (0.03), and 0.64 (0.03) for PREP-S in combination with PlGF, and sFlt-1:PlGF, respectively. Angiogenic biomarkers do not add to clinical assessment to help determine need for delivery for women with late preterm pre-eclampsia. Existing models developed in women with early-onset pre-eclampsia to predict complications cannot be used to predict clinically indicated need for delivery in women with late preterm pre-eclampsia.

A prospective study of placental growth factor in twin pregnancy and development of a dichorionic twin pregnancy specific reference range.

To develop a dichorionic twin pregnancy specific reference range for placental growth factor (PlGF), and to compare gestation-specific placental growth factor levels in twin pregnancies later complicated by pre-eclampsia, hypertensive disorder of pregnancy or fetal growth restriction with control pregnancies. Prospective observational study. Single large tertiary maternity unit in Ireland. Women with a twin pregnancy. Consenting pregnant women, across a variety of gestations, had a single blood sample taken at one time-point only during their pregnancy. The plasma was initially biobanked and PlGF was measured later in batches using the point of care Triage® PlGF test. Development of pre-eclampsia, hypertensive disorder of pregnancy or fetal growth restriction. Placental growth factor levels in uncomplicated dichorionic twin pregnancies were significantly lower in the women who later developed pre-eclampsia than in the controls at all gestational intervals. In those that later developed any hypertensive disorder of pregnancy, median PlGF was lower only in those recruited before 24weeks of gestation, whereas in infants with a customised birthweight below the third centile, PlGF was lower only in those sampled after 24weeks of gestation. Placental growth factor levels in twin pregnancy differ significantly between those women with a pregnancy that will later be complicated by pre-eclampsia and those that will not. This difference is present many weeks before clinical signs or symptoms of disease are present. Using cross-sectional values from uncomplicated twin pregnancies, we have developed a dichorionic twin pregnancy specific reference range for PlGF. Placental growth factor levels in twin pregnancy differ significantly between women that will later develop pre-eclampsia and those that will not.