The prediction of fetal death with a simple maternal blood test at 24-28 weeks: a role for angiogenic index-1 (PlGF/sVEGFR-1 ratio)

Abstract

Objective To determine if maternal plasma concentrations of angiogenic and anti-angiogenic factors measured at 24–28 weeks of gestation can predict subsequent fetal death. Methods 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 (PlGF), soluble endoglin (sEng), and soluble vascular endothelial growth factor receptor-1 (sVEGFR-1) concentrations were measured by ELISA assays. Quantiles of the analyte concentrations (or concentration ratios) were estimated as a function of gestational age among women who delivered live neonates but did not develop preeclampsia or deliver small-for-gestational–age (SGA) newborns. A positive test was defined as analyte concentrations (or ratios) <2.5th and 10th centiles [PlGF, PlGF/sVEGFR-1 (angiogenic index-1), and PlGF/sEng)] or >90th and 97.5th centiles (sVEGFR-1 and sEng). 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 prior to 28 weeks and eight at or after 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 before 28 weeks and 87.5% (7/8) of those who had this complication at or after 28 weeks of gestation. The maternal plasma angiogenic index-1 value was below the 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% CI, 7.7–27.7) and a relative risk of 29.1 (95% CI, 8.8–97.1), followed by sEng >97.5thcentile and PlGF/sEng <2.5th, both with a positive likelihood ratio of 13.7 (95% CI, 7.3–25.8) and a relative risk of 27.4 (95% CI, 8.2–91.2). Among women without a fetal death whose plasma angiogenic index-1 concentration ratio was below the 2.5th centile, 61% (19/31) developed preeclampsia or delivered an SGA neonate; when the 10th centile was used as the cut-off, 37% (34/92) of women had these adverse outcomes. Conclusions 1) A maternal plasma angiogenic index-1 value below the 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.

A prediction model for short-term neonatal outcomes in severe early-onset fetal growth restriction

“…With regards to prediction of low birth weight, the most effective markers to date appears to be PlGF [16][17][18] . A panel of angiogenic biomarkers, including PlGF and sFlt-1, taken at 24-28 weeks of gestation appears to be a good predictor of subsequent fetal demise (Relative risk of 29.1) when the biomarkers are grossly abnormal 19 . Furthermore, when PlGF/sFlt-1 ratio at [30][31][32][33][34] weeks of gestation is characterized as grossly abnormal (<0.12 MoM) it appears to be associated with subsequent stillbirth (80% sensitivity, 94% specificity) 20 .…”

Screening for fetal growth restriction using fetal biometry combined with maternal biomarkers

“…63 Moreover, extremes of the ratio have also been associated with the subsequent risk of intrauterine fetal death. 64 Mothers with a reduced rate of decrease of the antiangiogenic factor sENG between the first and second trimesters had a higher risk of adverse pregnancy outcome, including SGA (BW <10th centile). 65 Moreover, as mentioned above, maternal plasma sENG concentrations remained elevated throughout the second and third trimester in patients destined to deliver a SGA neonate.…”

The ability of late pregnancy maternal tests to predict adverse pregnancy outcomes associated with placental dysfunction (specifically fetal growth restriction and pre-eclampsia): a protocol for a systematic review and meta-analysis of prognostic accuracy studies

“…There is most evidence to support the use of late pregnancy maternal tests for the prediction of pre-eclampsia, e.g., tests based upon placental growth factor (PlGF), but other studies also report benefits in high-risk and unselected populations for the prediction of delivering a SGA infant [18,20]. Screening in late pregnancy using maternal tests to predict stillbirth is limited to a few small studies, and results are conflicting [20][21][22].…”