Urinary Placental Growth Factor for Prediction of Placental Adverse Outcomes in High-Risk Pregnancies.

OBJECTIVE: To evaluate whether urinary levels of placental growth factor (PlGF) during pregnancy are associated with the subsequent development of composite adverse outcomes (preeclampsia, fetal growth restriction, placental abruption, perinatal death, maternal death) occurring at less than 34 weeks of gestation. METHODS: This is a preplanned ancillary study of the Heparin-Preeclampsia trial, a randomized trial in pregnant women with a history of severe early-onset preeclampsia (less than 34 weeks of gestation). In the parent study, all women were treated with aspirin and then randomized to receive either low-molecular-weight (LMW) heparin or aspirin alone. For this substudy we measured urinary levels of PlGF and urinary creatinine at the following gestational windows: 10-13 6/7, 14-17 6/7, 18-21 6/7, 22-25 6/7, 26-29 6/7, 30-33 6/7, and 34-37 6/7 weeks of gestation. RESULTS: Urine samples were available from 187 patients: LMW heparin plus aspirin (n=93) and aspirin alone (n=94). The two groups had comparable baseline characteristics and had similar adverse composite outcomes at less than 34 weeks of gestation (14/93 [15.1%] vs 11/94 [11.7%]; P=.50). There were no significant differences in urine PlGF levels in the patients who received LMW heparin plus aspirin compared with those who received aspirin alone. However, median [interquartile range] urinary PlGF/creatinine concentrations (pg/mg) measured at mid-pregnancy (22-26 weeks of gestation) were significantly lower among women who developed composite adverse outcome at less than 34 weeks of gestation (42.7 [32.4-80.8] vs 255.6 [118.7-391.8] P<.001) and significantly lower among women who developed preeclampsia at less than 34 weeks of gestation (42.7 [27.5-80.7] vs 244.6 [112.9-390.6] P<.001). For a fixed false-positive rate of 10% the sensitivity of urinary PlGF concentrations at mid-pregnancy was 75.2% (area under the curve 0.93) for the subsequent development of composite adverse outcomes. CONCLUSION: Decreased urinary PlGF at mid-gestation (22-26 weeks of gestation) is associated with the subsequent development of preeclampsia-related adverse outcomes at less than 34 weeks of gestation. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT00986765.

Angiogenic Factor Profiles in Pregnant Women With a History of Early-Onset Severe Preeclampsia Receiving Low-Molecular-Weight Heparin Prophylaxis.

OBJECTIVE: To evaluate whether daily low-molecular-weight (LMW) heparin prophylaxis during pregnancy alters profile of circulating angiogenic factors that have been linked with the pathogenesis of preeclampsia and fetal growth restriction. METHODS: This is a planned ancillary study of the Heparin-Preeclampsia trial, a randomized trial in pregnant women with a history of severe early-onset preeclampsia (less than 34 weeks of gestation). In the parent study, all women were treated with aspirin and then randomized to receive LMW heparin or aspirin alone. In this study, we measured serum levels of circulating angiogenic factors (soluble fms-like tyrosine kinase-1, placental growth factor, and soluble endoglin by immunoassay) at the following gestational windows: 10-13 6/7 weeks, 14-17 6/7 weeks, 18-21 6/7 weeks, 22-25 6/7 weeks, 26-29 6/7 weeks, 30-33 6/7 weeks, and 34-37 6/7 weeks. RESULTS: Samples were available from 185 patients: LMW heparin+aspirin (n=92) and aspirin alone (n=93). The two groups had comparable baseline characteristics and had similar adverse composite outcomes (35/92 [38.0%] compared with 36/93 [38.7%]; P=.92). There were no significant differences in serum levels of soluble fms-like tyrosine kinase-1, placental growth factor, and soluble endoglin in the participants who received LMW heparin and aspirin compared with those who received aspirin alone regardless of gestational age period. Finally, women who developed an adverse composite outcome at less than 34 weeks of gestation demonstrated significant alterations in serum angiogenic profile as early as 10-13 6/7 weeks that was most dramatic 6-8 weeks preceding delivery. CONCLUSION: Prophylactic LMW heparin therapy when beginning from before 14 weeks of gestation with aspirin during pregnancy is not associated with an improved angiogenic profile. This may provide a molecular explanation for the lack of clinical benefit noted in recent trials. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT00986765.

Obstetric antiphospholipid syndrome: early variations of angiogenic factors are associated with adverse outcomes.

The prognostic value of angiogenic factors in newly pregnant women with obstetric antiphospholipid syndrome (oAPS) has not been documented. We observed 513 oAPS who experienced three consecutive spontaneous abortions before the 10th week of gestation or one fetal loss at or beyond the 10th week. We assessed the plasma concentrations of the proangiogenic factor placenta growth factor (PIGF) and of the antiangiogenic factor soluble fms-like tyrosine kinase-1 on the eve and on the 4th day of the low-molecular weight heparin-low-dose aspirin treatment. Placenta growth factor and fms-like tyrosine kinase-1 plasma concentrations showed marked increases. Treatment-associated variations of PIGF and of soluble fms-like tyrosine kinase-1 were antagonist risk factors for placenta-mediated complications (PMC) and for severe PMC, for fetal death, stillbirth and neonatal death. The ratio between PIGF increase and soluble fms-like tyrosine kinase-1 was a summary variable whose best cut-off values (1.944.10-2) had high negative predictive values for PMC (0.918) and may be used to help rule out the development of PMC in evolutive pregnancies after 19 completed weeks. The early variations of PIGF and soluble fms-like tyrosine kinase-1 concentrations in newly pregnant oAPS may help to detect patients at low risk of PMC. (clinicaltrials.gov identifier: 02855047).