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The prediction of fetal death with a simple maternal blood test at 20-24 weeks: a role for angiogenic index-1 (PlGF/sVEGFR-1 ratio).

ABSTRACT: BACKGROUND:Fetal death is an obstetrical syndrome that annually affects 2.4 to 3 million pregnancies worldwide, including more than 20,000 in the United States each year. Currently, there is no test available to identify patients at risk for this pregnancy complication. OBJECTIVE:We sought to determine if maternal plasma concentrations of angiogenic and antiangiogenic factors measured at 24-28 weeks of gestation can predict subsequent fetal death. STUDY DESIGN:A case-cohort study was designed to include 1000 randomly selected subjects and all remaining fetal deaths (cases) from a cohort of 4006 women with a singleton pregnancy, enrolled at 6-22 weeks of gestation, in a pregnancy biomarker cohort study. The placentas of all fetal deaths were histologically examined by pathologists who used a standardized protocol and were blinded to patient outcomes. Placental growth factor, soluble endoglin, and soluble vascular endothelial growth factor receptor-1 concentrations were measured by enzyme-linked immunosorbent assays. Quantiles of the analyte concentrations (or concentration ratios) were estimated as a function of gestational age among women who delivered a live neonate but did not develop preeclampsia or deliver a small-for-gestational-age newborn. A positive test was defined as analyte concentrations (or ratios) <2.5th and 10th centiles (placental growth factor, placental growth factor/soluble vascular endothelial growth factor receptor-1 [angiogenic index-1] and placental growth factor/soluble endoglin) or >90th and 97.5th centiles (soluble vascular endothelial growth factor receptor-1 and soluble endoglin). Inverse probability weighting was used to reflect the parent cohort when estimating the relative risk. RESULTS:There were 11 fetal deaths and 829 controls with samples available for analysis between 24-28 weeks of gestation. Three fetal deaths occurred <28 weeks and 8 occurred ?28 weeks of gestation. The rate of placental lesions consistent with maternal vascular underperfusion was 33.3% (1/3) among those who had a fetal death <28 weeks and 87.5% (7/8) of those who had this complication ?28 weeks of gestation. The maternal plasma angiogenic index-1 value was <10th centile in 63.6% (7/11) of the fetal death group and in 11.1% (92/829) of the controls. The angiogenic index-1 value was <2.5th centile in 54.5% (6/11) of the fetal death group and in 3.7% (31/829) of the controls. An angiogenic index-1 value <2.5th centile had the largest positive likelihood ratio for predicting fetal death >24 weeks (14.6; 95% confidence interval, 7.7-27.7) and a relative risk of 29.1 (95% confidence interval, 8.8-97.1), followed by soluble endoglin >97.5th centile and placental growth factor/soluble endoglin <2.5th, both with a positive likelihood ratio of 13.7 (95% confidence interval, 7.3-25.8) and a relative risk of 27.4 (95% confidence interval, 8.2-91.2). Among women without a fetal death whose plasma angiogenic index-1 concentration ratio was <2.5th centile, 61% (19/31) developed preeclampsia or delivered a small-for-gestational-age neonate; when the 10th centile was used as the cut-off, 37% (34/92) of women had these adverse outcomes. CONCLUSION:(1) A maternal plasma angiogenic index-1 value <2.5th centile (0.126) at 24-28 weeks of gestation carries a 29-fold increase in the risk of subsequent fetal death and identifies 55% of subsequent fetal deaths with a false-positive rate of 3.5%; and (2) 61% of women who have a false-positive test result will subsequently experience adverse pregnancy outcomes.

SUBMITTER: Chaiworapongsa T

PROVIDER: S-EPMC5951183 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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The prediction of fetal death with a simple maternal blood test at 20-24 weeks: a role for angiogenic index-1 (PlGF/sVEGFR-1 ratio).

Chaiworapongsa Tinnakorn T Romero Roberto R Erez Offer O Tarca Adi L AL Conde-Agudelo Agustin A Chaemsaithong Piya P Chaemsaithong Piya P Kim Chong Jai CJ Kim Yeon Mee YM Kim Jung-Sun JS Yoon Bo Hyun BH Hassan Sonia S SS Yeo Lami L Korzeniewski Steven J SJ

American journal of obstetrics and gynecology 20171013 6

<h4>Background</h4>Fetal death is an obstetrical syndrome that annually affects 2.4 to 3 million pregnancies worldwide, including more than 20,000 in the United States each year. Currently, there is no test available to identify patients at risk for this pregnancy complication.<h4>Objective</h4>We sought to determine if maternal plasma concentrations of angiogenic and antiangiogenic factors measured at 24-28 weeks of gestation can predict subsequent fetal death.<h4>Study design</h4>A case-cohort ...[more]

PMID: 29037482

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Project description:IntroductionThe velocity of fetal deterioration in fetal growth restriction is extremely variable, which makes monitoring and counseling very challenging. The soluble fms-like tyrosine kinase to placental growth factor (sFlt1/PlGF) ratio provides a readout of the vasoactive environment that correlates with preeclampsia and fetal growth restriction and that could be useful to predict fetal deterioration. Previous studies showed a correlation between higher sFlt1/PlGF ratios and lower gestational ages at birth, although it is unclear whether this is due to the increased incidence of preeclampsia. Our goal was to evaluate whether the sFlt1/PlGF ratio predicts faster fetal deterioration in early fetal growth restriction.Material and methodsThis was a historical cohort study in a tertiary maternity hospital. Data from singleton pregnancies with early fetal growth restriction (diagnosed before 32 gestational weeks) confirmed after birth monitored between January 2016 and December 2020 were retrieved from clinical files. Cases of chromosomal/fetal abnormalities, infection and medical terminations of pregnancy were excluded. The sFlt1/PlGF ratio was acquired at diagnosis of early fetal growth restriction in our unit. The correlation of log10 sFlt1/PlGF with latency to delivery/fetal demise was assessed with linear, logistic (positive sFlt1/PlGF if >85) and Cox regression excluding deliveries for maternal conditions and controlling for preeclampsia, gestational age at time of ratio test, maternal age and smoking during pregnancy. Receiver-operating characteristic (ROC) analysis tested the performance of sFlt1/PlGF ratio in predicting delivery for fetal reasons in the following week.Results125 patients were included. Mean sFlt1/PlGF ratio was 91.2 (SD 148.7) and 28% of patients had a positive ratio. A higher log10 sFlt1/PlGF ratio predicted shorter latency for delivery/fetal demise in linear regression after controlling for confounders, β = -3.001, (-3.713 to -2.288). Logistic regression with ratio positivity confirmed these findings (latency for delivery 5.7 ± 3.32 weeks for ratios ≤85 vs 1.9 ± 1.52 weeks for ratios >85); β = -0.698 (-1.064 to -0.332). Adjusted Cox regression showed that a positive ratio confers a significantly positive hazard ratio (HR) for earlier delivery/fetal demise, HR 9.869 (5.061-19.243). ROC analysis showed an area under the curve of 0.847 (SE ± 0.06).ConclusionssFlt1/PlGF ratio is correlated with faster fetal deterioration in early fetal growth restriction, independently of preeclampsia.

Project description:BackgroundFetal growth restriction is a major determinant of perinatal morbidity and mortality. This condition has no gold standard definition, but a widely used proxy is delivery of a small for gestational age infant (<10th percentile) combined with an adverse pregnancy outcome. Effective screening for fetal growth restriction is an area of unmet clinical need. We aimed to determine the diagnostic effectiveness of a combination of ultrasonic fetal biometry and measurement of the ratio of soluble fms-like tyrosine kinase receptor 1 (sFLT1) to placental growth factor (PlGF) in predicting adverse pregnancy outcomes associated with delivery of a small for gestational age infant.MethodsIn this prospective cohort study, using serial antenatal blood sampling and blinded ultrasound scans, we investigated the association between the combination of an elevated sFLT1/PlGF ratio (>85th percentile) and ultrasonically suspected small for gestational age (<10th percentile) at both 28 and 36 weeks of gestational age. The outcome following the 28 week measurement was preterm delivery of a small for gestational age infant. The outcome following the 36 week measurement was subsequent delivery of a small for gestational infant associated with maternal pre-eclampsia or perinatal morbidity or mortality. All definitions of exposure and outcome were predefined before we did our data analysis.FindingsBetween Jan 14, 2008, and July 31, 2012, we recruited 4512 nulliparous women. 4098 women (91%) had a sFLT1/PlGF ratio measurement and estimated fetal weight at 28 or 36 weeks of gestational age, and outcome data available. 3981 women were analysed for 28 weeks of gestational age measurements and 3747 women were analysed for 36 weeks of gestational age measurements. At 28 weeks, 47 (1%) of 3981 women had the combination of ultrasonic small for gestational age and an elevated sFLT1/PlGF ratio. The positive likelihood ratio for preterm delivery of a small for gestational age infant associated with this combination was 41·1 (95% CI 23·0-73·6), the sensitivity was 38·5% (21·1-59·3), the specificity was 99·1% (98·7-99·3), and the positive predictive value was 21·3% (11·6-35·8). At 36 weeks, 102 (3%) of 3747 women had the combination of ultrasonic small for gestational age and an elevated sFLT1/PlGF ratio. The positive likelihood ratio for delivery of a small for gestational age infant associated with maternal pre-eclampsia or perinatal morbidity or mortality was 17·5 (95% CI 11·8-25·9), the sensitivity was 37·9% (26·1-51·4), the specificity was 97·8% (97·3-98·3), and the positive predictive value was 21·6% (14·5-30·8). The positive likelihood ratios at both gestational ages were higher than previously described definitions of suspected fetal growth restriction using purely ultrasonic assessment.InterpretationThe combination of ultrasonically suspected small for gestational age plus an elevated sFLT1/PlGF ratio in unselected nulliparous women identified a relatively small proportion of women who have high absolute risks of clinically important adverse outcomes. Screening and intervention based on this approach could result in net benefit and this could be an appropriate subject for a randomised controlled trial.FundingNIHR Cambridge Comprehensive Biomedical Research Centre, Medical Research Council, and Stillbirth and neonatal death society (Sands).

Dataset Information

The prediction of fetal death with a simple maternal blood test at 20-24 weeks: a role for angiogenic index-1 (PlGF/sVEGFR-1 ratio).

Publications

The prediction of fetal death with a simple maternal blood test at 20-24 weeks: a role for angiogenic index-1 (PlGF/sVEGFR-1 ratio).

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